6-(poly-substituted aryl)-4-aminopicolinates and their use as herbicides

ABSTRACT

4-Aminopicolinic acids having tri- and tetra-substituted aryl substituents in the 6-position, and their amine and acid derivatives, are potent herbicides demonstrating a broad spectrum of weed control.

This application claims the benefit of U.S. Provisional ApplicationsSer. Nos. 60/758,701 filed on Jan. 13, 2006 and 60/850,145 filed Oct. 6,2006.

BACKGROUND OF THE INVENTION

This invention relates to certain novel 6-(poly-substitutedaryl)-4-aminopicolinates and their derivatives and to the use of thesecompounds as herbicides.

A number of picolinic acids and their pesticidal properties have beendescribed in the art. U.S. Pat. No. 6,784,137 B2 discloses a genus of6-aryl-4-aminopicolinic acids and their derivatives and their use asherbicides. It has now been discovered that certain particularsubclasses of the genus disclosed in '137 have greatly improvedherbicidal activity and selectivity.

SUMMARY OF THE INVENTION

It has now been found that certain 6-(poly-substitutedaryl)-4-aminopicolinic acids and their derivatives are superiorherbicides with a broad spectrum of weed control against woody plants,grasses and sedges as well as broadleaves and with excellent cropselectivity. The compounds further possess excellent toxicological orenvironmental profiles.

The invention includes compounds of Formula I:

wherein

Q₁ represents H or F;

Q₂ represents a halogen with the proviso that when Q₁ is H then Q₂ is Clor Br;

R₁ and R₂ independently represent H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, hydroxy, C₁-C₆ alkoxy, amino, C₁-C₆ acyl, C₁-C₆ carboalkoxy,C₁-C₆ alkylcarbamyl, C₁-C₆ alkylsulfonyl, C₁-C₆ trialkylsilyl or C₁-C₆dialkyl phosphonyl or R₁ and R₂ taken together with N represent a 5- or6-membered saturated ring; and

Ar represents a polysubstituted aryl group selected from the groupconsisting of

wherein

W₁ represents halogen;

X represents F, Cl, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy-substituted C₁-C₄ alkyl, C₁-C₄ alkoxy-substituted C₁-C₄alkoxy, —CN, —NR₃R₄ or fluorinated acetyl or propionyl;

Y₁ represents C₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen or —CN, or,

when X₁ and Y₁ are taken together, represents —O(CH₂)_(n)O— wherein n=1or 2; and

R₃ and R₄ independently represent H or C₁-C₄ alkyl;

wherein

W₂ represents F or Cl;

X₂ represents F, Cl, —CN, —NO₂, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy-substituted C₁-C₄ alkyl, C₁-C₄alkoxy-substituted C₁-C₄ alkoxy, —NR₃R₄ or fluorinated acetyl orpropionyl;

Y₂ represents halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or —CN, or, when W₂represents F, X₂ and Y₂ taken together represent —O(CH₂)_(n)O— whereinn=1 or 2; and

R₃ and R₄ independently represent H or C₁-C₆ alkyl; and

wherein

Y₃ represents halogen, —CN or —CF₃;

Z₃ represents F, Cl, —CN, —NO₂, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy-substituted C₁-C₄ alkyl, C₁-C₄alkoxy-substituted C₁-C₄ alkoxy, —NR₃R₄ or fluorinated acetyl orpropionyl; and

R₃ and R₄ independently represent H, or C₁-C₆ alkyl; and agriculturallyacceptable derivatives of the carboxylic acid group.

Compounds of Formula I wherein Y₁, Y₂ or Y₃ represents Cl, Br or CF₃,wherein W₁ or W₂ represents Cl or F, wherein X₁ or X₂ represents C₁-C₄alkoxy, C₁-C₄ thioalkoxy, C₁-C₄ haloalkyl or NR₃R₄, and wherein Zrepresents C₁-C₄ alkoxy, C₁-C₄ thioalkoxy, C₁-C₄ haloalkyl or NR₃R₄ areindependently preferred.

The invention includes herbicidal compositions comprising a herbicidallyeffective amount of a compound of Formula I and agriculturallyacceptable derivatives of the carboxylic acid group in admixture with anagriculturally acceptable adjuvant or carrier. The invention alsoincludes a method of use of the compounds and compositions of thepresent invention to kill or control undesirable vegetation byapplication of an herbicidal amount of the compound to the vegetation orto the locus of the vegetation as well as to the soil prior to emergenceof the vegetation. The invention further includes intermediates for thepreparation of the compounds.

DETAILED DESCRIPTION OF THE INVENTION

The herbicidal compounds of the present invention are derivatives of4-aminopicolinic acids of Formula II:

wherein

Q₁ represents H or F;

Q₂ represents a halogen with the proviso that when Q₁ is H then Q₂ is Clor Br; and

Ar represents a polysubstituted aryl group selected from the groupconsisting of

wherein

W₁ represents halogen;

X₁ represents F, Cl, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy-substituted C₁-C₄ alkyl, C₁-C₄ alkoxy-substituted C₁-C₄alkoxy, —CN, fluorinated acetyl or propionyl, or —NR₃R₄;

Y¹ represents C₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen or —CN or,

when X₁ and Y₁ are taken together, represents —O(CH₂)_(n)O— wherein n=1or 2; and

R₃ and R₄ independently represent H, or C₁-C₄ alkyl;

wherein

W₂ represents F or Cl;

X₂ represents, F, Cl, —CN, —NO₂, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy-substituted C₁-C₄ alkyl, C₁-C₄alkoxy-substituted C₁-C₄ alkoxy, fluorinated acetyl or propionyl, or—NR₃R₄;

Y₂ represents halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or —CN, or,

when W₂ represents F, X₂ and Y₂ taken together represent —O(CH₂)_(n)O—wherein n=1 or 2; and

R₃ and R₄ independently represent H, or C₁-C₆ alkyl; and

wherein

Y₃ represents halogen, —CN or —CF₃;

Z₃ represents F, Cl, —CN, —NO₂, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy-substituted C₁-C₄ alkyl, C₁-C₄alkoxy-substituted C₁-C₄ alkoxy fluorinated acetyl or propionyl, or—NR₃R₄; and

R₃ and R₄ independently represent H, or C₁-C₆ alkyl.

These compounds are characterized by possessing a Cl or F in the3-position, H or F in the 5-position and a tri- or tetra-substitutedaryl group in the 6-position of the pyridine ring. Compounds in which C1is in the 3-position and H is in the 5-position are generally preferred.Preferred substituted aryl groups include 2,3,4-trisubstituted,2-fluoro-4,5-trisubstituted and 2-fluoro-4,5,6-tetrasubstituted phenylgroups. Particularly preferred substituted aryl groups include thosewherein Y₁, Y₂ or Y₃ represents Cl, Br or CF₃, wherein W₁ or W₂represents Cl or F, wherein X₁ or X₂ represents C₁-C₄ alkoxy, C₁-C₄thioalkoxy, C₁-C₄ haloalkyl or NR₃R₄, and wherein Z represents C₁-C₄alkoxy, C₁-C₄ thioalkoxy, C₁-C₄ haloalkyl or NR₃R₄.

The amino group at the 4-position of the pyridine ring can beunsubstituted or substituted with one or more C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, hydroxy, C₁-C₆ alkoxy or amino substituents. Theamino group can be further derivatized as an amide, a carbamate, a urea,a sulfonamide, a silylamine or a phosphoramidate. Such derivatives arecapable of breaking down into the amine. An unsubstituted amino group ispreferred.

The carboxylic acids of Formula I are believed to be the compounds thatactually kill or control undesirable vegetation and are typicallypreferred. Analogs of these compounds in which the acid group of thepicolinic acid is derivatized to form a related substituent that can betransformed within plants or the environment to a acid group possessessentially the same herbicidal effect and are within the scope of theinvention. Therefore, an “agriculturally acceptable derivative”, whenused to describe the carboxylic acid functionality at the 2-position, isdefined as any salt, ester, acylhydrazide, imidate, thioimidate,amidine, amide, orthoester, acylcyanide, acyl halide, thioester,thionoester, dithiolester, nitrile or any other acid derivative wellknown in the art which (a) does not substantially affect the herbicidalactivity of the active ingredient, i.e., the 6-aryl-4-aminopicolinicacid, and (b) is or can be hydrolyzed, oxidized or metabolized in plantsor soil to the picolinic acid of Formula I that, depending upon the pH,is in the dissociated or the undissociated form. The preferredagriculturally acceptable derivatives of the carboxylic acid areagriculturally acceptable salts, esters and amides. Likewise, an“agriculturally acceptable derivative”, when used to describe the aminefunctionality at the 4-position, is defined as any salt, silylamine,phosphorylamine, phosphinimine, phosphoramidate, sulfonamide,sulfilimine, sulfoximine, aminal, hemiaminal, amide, thioamide,carbamate, thiocarbamate, amidine, urea, imine, nitro, nitroso, azide,or any other nitrogen containing derivative well known in the art which(a) does not substantially affect the herbicidal activity of the activeingredient, i.e., the 6-aryl-4-aminopicolinic acid, and (b) is or can behydrolyzed in plants or soil to a free amine of Formula II. N-Oxides,which are also capable of breaking into the parent picoline of FormulaII, are also covered by the scope of this invention.

Suitable salts include those derived from alkali or alkaline earthmetals and those derived from ammonia and amines. Preferred cationsinclude sodium, potassium, magnesium, and aminium cations of theformula:R₅R₆R₇NH⁺wherein R₅, R₆, and R₇ each, independently represents hydrogen or C₁-C₁₂alkyl, C₃-C₁₂ alkenyl or C₃-C₁₂ alkynyl, each of which is optionallysubstituted by one or more hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio orphenyl groups, provided that R₅, R₆, and R₇ are sterically compatible.Additionally, any two of R₅, R₆, and R₇ together may represent analiphatic difunctional moiety containing 1 to 12 carbon atoms and up totwo oxygen or sulfur atoms. Salts of the compounds of Formula I can beprepared by treatment of compounds of Formula I with a metal hydroxide,such as sodium hydroxide, or an amine, such as ammonia, trimethylamine,diethanolamine, 2-methylthiopropylamine, bisallylamine,2-butoxyethylamine, morpholine, cyclododecylamine, or benzylamine. Aminesalts are often preferred forms of the compounds of Formula I becausethey are water-soluble and lend themselves to the preparation ofdesirable aqueous based herbicidal compositions.

Suitable esters include those derived from C₁-C₁₂ alkyl, C₃-C₁₂ alkenylor C₃-C₁₂ alkynyl alcohols, such as methanol, iso-propanol, butanol,2-ethylhexanol, butoxyethanol, methoxypropanol, allyl alcohol, propargylalcohol or cyclohexanol. Esters can be prepared by coupling of thepicolinic acid with the alcohol using any number of suitable activatingagents such as those used for peptide couplings such asdicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI), byreacting the corresponding acid chloride of a picolinic acid of FormulaI with an appropriate alcohol or by reacting the corresponding picolinicacid of Formula I with an appropriate alcohol in the presence of an acidcatalyst. Suitable amides include those derived from ammonia or fromC₁-C₁₂ alkyl, C₃-C₁₂ alkenyl or C₃-C₁₂ alkynyl mono- or di-substitutedamines, such as but not limited to dimethylamine, diethanolamine,2-methylthiopropylamine, bisallylamine, 2-butoxyethylamine,cyclododecylamine, benzylamine or cyclic or aromatic amines with orwithout additional heteroatoms such as but not limited to aziridine,azetidine, pyrrolidine, pyrrole, imidazole, tetrazole or morpholine.Amides can be prepared by reacting the corresponding picolinic acidchloride, mixed anhydride, or carboxylic ester of Formula I with ammoniaor an appropriate amine.

The terms “alkyl”, “alkenyl” and “alkynyl”, as well as derivative termssuch as “alkoxy”, “acyl”, “alkylthio” and “alkylsulfonyl”, as usedherein, include within their scope straight chain, branched chain andcyclic moieties. The terms “alkenyl” and “alkynyl” are intended toinclude one or more unsaturated bonds.

The term “aryl”, as well as derivative terms such as “aryloxy”, refersto a phenyl.

Unless specifically limited otherwise, the term “halogen” includingderivative terms such as “halo” refers to fluorine, chlorine, bromine,and iodine. The terms “haloalkyl” and “haloalkoxy” refer to alkyl andalkoxy groups substituted with from 1 to the maximum possible number ofhalogen atoms.

The compounds of Formula I can be made using well-known chemicalprocedures. The required starting materials are commercially availableor readily synthesized utilizing standard procedures.

The 6-substituted arylpicolines of Formula I can be prepared from anumber of ways, which are well known in the art, e.g., by reaction of anappropriately substituted pyridine with a facile leaving group in the6-position (III) with an organometallic compound of the type (IV) in aninert solvent in the presence of a transition metal catalyst.

In this case “L” can be chlorine, bromine, iodo ortrifluoromethanesulfonate, “Metal” can be Mg-halide, Zn-halide,tri-(C₁-C₄ alkyl)tin, lithium, copper, or B(OR₈)(OR₉), where R₈ and R₉are, independent of one another, hydrogen, C₁-C₄ alkyl, or when takentogether form an ethylene or propylene group, and “Catalyst” is atransition metal catalyst, in particular a palladium catalyst such aspalladium diacetate, bis(triphenylphosphine)palladium(II) dichloride, ora nickel catalyst such as nickel(II) acetylacetonate,bis(triphenylphosphine)nickel(II) chloride.

Alternatively, compounds of Formula I can be prepared by reaction of anappropriately substituted 6-metal substituted pyridine (V) with an arylcompound of the type (VI) in an inert solvent in the presence of atransition metal catalyst.

In this case “L” can be chlorine, bromine, iodo ortrifluoromethanesulfonate and “Metal” can be Mg-halide, Zn-halide,tri-(C₁-C₄ alkyl)tin, lithium, copper, or B(OR₈)(OR₉), where R₈ and R₉are independent of one another, hydrogen, C₁-C₄ alkyl, or when takentogether form an ethylene or propylene group, and “Catalyst” can be atransition metal catalyst, in particular a palladium catalyst such aspalladium diacetate, bis(triphenylphosphine)palladium(II)dichloride, ora nickel catalyst such as nickel(II)acetylacetonate,bis(triphenylphosphine)nickel(II) chloride.

Reactions with boronic acids or esters are well known as exemplified bythe following references:

-   (1) W. J. Thompson and J. Gaudino, J. Org. Chem., 49, 5223 (1984);-   (2) S. Gronowitz and K. Lawitz, Chem. Scr., 24, 5 (1984);-   (3) S. Gronowitz et al., Chem. Scr., 26, 305 (1986);-   (4) J. Stavenuiter et al., Heterocycles, 26, 2711 (1987);-   (5) V. Snieckus et al., Tetrahedron Letters, 28, 5093 (1987);-   (6) V. Snieckus et al., Tetrahedron Letters, 29, 2135 (1988);-   (7) M. B. Mitchell et al., Tetrahedron Letters, 32, 2273 (1991);    Tetrahedron, 48, 8117 (1992);-   (8) JP-A 93/301870.

Reactions with Grignard compounds (metal=Mg-Hal):

-   (9) L. N. Pridgen, J. Heterocyclic Chem., 12, 443 (1975);-   (10) M. Kumada et al., Tetrahedron Letters, 21, 845 (1980);-   (11) A. Minato et al., J. Chem. Soc. Chem. Commun., 5319 (1984).

Reaction with organozinc compounds (metal=Zn-Hal):

-   (12) A. S. Bell et al., Synthesis, 843 (1987);-   (13) A. S. Bell et al., Tetrahedron Letters, 29, 5013 (1988);-   (14) J. W. Tilley and S. Zawoiski, J. Org. Chem., 53, 386 (1988);    see also ref. (9).

Reactions with organotin compounds (metal=Sn(C₁-C₄(alkyl)₃):

-   (15) T. R. Bailey et al., Tetrahedron Letters, 27, 4407 (1986);-   (16) Y. Yamamoto et al., Synthesis, 564 (1986); see also ref. (6)

The coupling of III+IV, or V+VI may, where appropriate, be followed byreactions on either ring to obtain further derivatives of the compoundsof Formula I.

Appropriately substituted pyridines of Formula III where L is chloro,bromo, iodo or trifluoromethanesulfonate can be easily obtain bywell-known methods; see WO 0151468. For example, 6-bromo analogs can beprepared by the reduction of several key intermediates, e.g., thecorresponding 6-bromo-4-azido, 6-bromo-4-nitro, and 6-bromo-4-nitropyridine N-oxide analogs. These intermediates, in turn, can be preparedeither by nucleophilic displacement of 6-bromo-4-halo analogs with NaN₃or by electrophilic nitration of the corresponding6-bromopyridine-N-oxides. Alternatively, such analogs can be prepared bydirect amination of the corresponding 4,6-dibromo analogs.

4-N-Amide, carbamate, urea, sulfonamide, silylamine and phosphoramidateamino derivatives can be prepared by the reaction of the free aminocompound with, for example, a suitable acid halide, chloroformate,carbamyl chloride, sulfonyl chloride, silyl chloride or chlorophosphate.

Substituted 4-amino analogs can be prepared by reacting thecorresponding 4-halopyridine-2-carboxylate or any other displaceable4-substituent with the substituted amine.

The compounds of Formula I, obtained by any of these processes, can berecovered by conventional means. Typically, the reaction mixture isacidified with an aqueous acid, such as hydrochloric acid, and extractedwith an organic solvent, such as ethyl acetate or methylene chloride.The organic solvent and other volatiles can be removed by distillationor evaporation to obtain the desired compound of Formula I, which can bepurified by standard procedures, such as by recrystallization orchromatography.

The compounds of Formula I have been found to be useful as pre-emergenceand post-emergence herbicides. They can be employed at non-selective(higher) rates of application to control a broad spectrum of thevegetation in an area or at lower rates of application for the selectivecontrol of undesirable vegetation. Areas of application include pastureand rangelands, roadsides and rights of way, power lines and anyindustrial areas where control of undesirable vegetation is desirable.Another use is the control of unwanted vegetation in crops such as corn,rice and cereals. They can also be used to control undesirablevegetation in tree crops such as citrus, apple, rubber, oil palm,forestry and others. It is usually preferred to employ the compoundspost-emergence. It is further usually preferred to use the compounds tocontrol a wide spectrum of woody plants, broadleaf and grass weeds, andsedges. Use of the compounds to control undesirable vegetation inestablished crops is especially indicated. While each of the6-aryl-4-aminopicolinate compounds encompassed by Formula I is withinthe scope of the invention, the degree of herbicidal activity, the cropselectivity, and the spectrum of weed control obtained varies dependingupon the substituents present. An appropriate compound for any specificherbicidal utility can be identified by using the information presentedherein and routine testing.

The term herbicide is used herein to mean an active ingredient thatkills, controls or otherwise adversely modifies the growth of plants. Anherbicidally effective or vegetation controlling amount is an amount ofactive ingredient which causes an adversely modifying effect andincludes deviations from natural development, killing, regulation,desiccation, retardation, and the like. The terms plants and vegetationinclude germinant seeds, emerging seedlings and established vegetation.

Herbicidal activity is exhibited by the compounds of the presentinvention when they are applied directly to the plant or to the locus ofthe plant at any stage of growth or before planting or emergence. Theeffect observed depends upon the plant species to be controlled, thestage of growth of the plant, the application parameters of dilution andspray drop size, the particle size of solid components, theenvironmental conditions at the time of use, the specific compoundemployed, the specific adjuvants and carriers employed, the soil type,and the like, as well as the amount of chemical applied. These and otherfactors can be adjusted as is known in the art to promote non-selectiveor selective herbicidal action. Generally, it is preferred to apply thecompounds of Formula I postemergence to relatively immature undesirablevegetation to achieve the maximum control of weeds.

Application rates of about 0.1 to about 1,000 g/Ha are generallyemployed in postemergence operations; for preemergence applications,rates of about 1 to about 2,000 g/Ha are generally employed. The higherrates designated generally give non-selective control of a broad varietyof undesirable vegetation. The lower rates typically give selectivecontrol and can be employed in the locus of crops.

The herbicidal compounds of the present invention are often applied inconjunction with one or more other herbicides to control a wider varietyof undesirable vegetation. When used in conjunction with otherherbicides, the presently claimed compounds can be formulated with theother herbicide or herbicides, tank mixed with the other herbicide orherbicides or applied sequentially with the other herbicide orherbicides. Some of the herbicides that can be employed in conjunctionwith the compounds of the present invention include: amide herbicidessuch as allidochlor, beflubutamid, benzadox, benzipram, bromobutide,cafenstrole, CDEA, chlorthiamid, cyprazole, dimethenamid,dimethenamid-P, diphenamid, epronaz, etnipromid, fentrazamide, flupoxam,fomesafen, halosafen, isocarbamid, isoxaben, napropamide, naptalam,pethoxamid, propyzamide, quinonamid and tebutam; anilide herbicides suchas chloranocryl, cisanilide, clomeprop, cypromid, diflufenican,etobenzanid, fenasulam, flufenacet, flufenican, mefenacet, mefluidide,metamifop, monalide, naproanilide, pentanochlor, picolinafen andpropanil; arylalanine herbicides such as benzoylprop, flampropandflamprop-M; chloroacetanilide herbicides such as acetochlor, alachlor,butachlor, butenachlor, delachlor, diethatyl, dimethachlor, metazachlor,metolachlor, S-metolachlor, pretilachlor, propachlor, propisochlor,prynachlor, terbuchlor, thenylchlor and xylachlor; sulfonanilideherbicides such as benzofluor, perfluidone, pyrimisulfan and profluazol;sulfonamide herbicides such as asulam, carbasulam, fenasulam andoryzalin; antibiotic herbicides such as bilanafos; benzoic acidherbicides such as chloramben, dicamba, 2,3,6-TBA and tricamba;pyrimidinyloxybenzoic acid herbicides such as bispyribac andpyriminobac; pyrimidinylthiobenzoic acid herbicides such as pyrithiobac;phthalic acid herbicides such as chlorthal; picolinic acid herbicidessuch as aminopyralid, clopyralid and picloram; quinolinecarboxylic acidherbicides such as quinclorac and quinmerac; arsenical herbicides suchas cacodylic acid, CMA, DSMA, hexaflurate, MAA, MAMA, MSMA, potassiumarsenite and sodium arsenite; benzoylcyclohexanedione herbicides such asmesotrione, sulcotrione, tefuryltrione and tembotrione; benzofuranylalkylsulfonate herbicides such as benfuresate and ethofumesate;carbamate herbicides such as asulam, carboxazole chlorprocarb,dichlormate, fenasulam, karbutilate and terbucarb; carbanilateherbicides such as barban, BCPC, carbasulam, carbetamide, CEPC,chlorbufam, chlorpropham, CPPC, desmedipham, phenisopham, phenmedipham,phenmedipham-ethyl, propham and swep; cyclohexene oxime herbicides suchas alloxydim, butroxydim, clethodim, cloproxydim, cycloxydim,profoxydim, sethoxydim, tepraloxydim and tralkoxydim;cyclopropylisoxazole herbicides such as isoxachlortole and isoxaflutole;dicarboximide herbicides such as benzfendizone, cinidon-ethyl, flumezin,flumiclorac, flumioxazin and flumipropyn; dinitroaniline herbicides suchas benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin,isopropalin, methalpropalin, nitralin, oryzalin, pendimethalin,prodiamine, profluralin and trifluralin; dinitrophenol herbicides suchas dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC, etinofen andmedinoterb; diphenyl ether herbicides such as ethoxyfen; nitrophenylether herbicides such as acifluorfen, aclonifen, bifenox,chlomethoxyfen, chlornitrofen, etnipromid, fluorodifen, fluoroglycofen,fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen,nitrofluorfen and oxyfluorfen; dithiocarbamate herbicides such asdazomet and metam; halogenated aliphatic herbicides such as alorac,chloropon, dalapon, flupropanate, hexachloroacetone, iodomethane, methylbromide, monochloroacetic acid, SMA and TCA; imidazolinone herbicidessuch as imazamethabenz, imazamox, imazapic, imazapyr, imazaquin andimazethapyr; inorganic herbicides such as ammonium sulfamate, borax,calcium chlorate, copper sulfate, ferrous sulfate, potassium azide,potassium cyanate, sodium azide, sodium chlorate and sulfuric acid;nitrile herbicides such as bromobonil, bromoxynil, chloroxynil,dichlobenil, iodobonil, ioxynil and pyraclonil; organophosphorusherbicides such as amiprofos-methyl, anilofos, bensulide, bilanafos,butamifos, 2,4-DEP, DMPA, EBEP, fosamine, glufosinate, glyphosate andpiperophos; phenoxy herbicides such as bromofenoxim, clomeprop, 2,4-DEB,2,4-DEP, difenopenten, disul, erbon, etnipromid, fenteracol andtrifopsime; phenoxyacetic herbicides such as 4-CPA, 2,4-D, 3,4-DA, MCPA,MCPA-thioethyl and 2,4,5-T; phenoxybutyric herbicides such as 4-CPB,2,4-DB, 3,4-DB, MCPB and 2,4,5-TB; phenoxypropionic herbicides such ascloprop, 4-CPP, dichlorprop, dichlorprop-P, 3,4-DP, fenoprop, mecopropand mecoprop-P; aryloxyphenoxypropionic herbicides such as chlorazifop,clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenoxaprop-P,fenthiaprop, fluazifop, fluazifop-P, haloxyfop, haloxyfop-P,isoxapyrifop, metamifop, propaquizafop, quizalofop, quizalofop-P andtrifop; phenylenediamine herbicides such as dinitramine and prodiamine;pyrazolyl herbicides such as benzofenap, pyrazolynate, pyrasulfotole,pyrazoxyfen, pyroxasulfone and topramezone; pyrazolylphenyl herbicidessuch as fluazolate and pyraflufen; pyridazine herbicides such ascredazine, pyridafol and pyridate; pyridazinone herbicides such asbrompyrazon, chloridazon, dimidazon, flufenpyr, metflurazon,norflurazon, oxapyrazon and pydanon; pyridine herbicides such asaminopyralid, cliodinate, clopyralid, dithiopyr, fluoroxypyr,haloxydine, picloram, picolinafen, pyriclor, thiazopyr and triclopyr;pyrimidinediamine herbicides such as iprymidam and tioclorim; quaternaryammonium herbicides such as cyperquat, diethamquat, difenzoquat, diquat,morfamquat and paraquat; thiocarbamate herbicides such as butylate,cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate,methiobencarb, molinate, orbencarb, pebulate, prosulfocarb,pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate andvernolate; thiocarbonate herbicides such as dimexano, EXD and proxan;thiourea herbicides such as methiuron; triazine herbicides such asdipropetryn, triaziflam and trihydroxytriazine; chlorotriazineherbicides such as atrazine, chlorazine, cyanazine, cyprazine,eglinazine, ipazine, mesoprazine, procyazine, proglinazine, propazine,sebuthylazine, simazine, terbuthylazine and trietazine; methoxytriazineherbicides such as atraton, methometon, prometon, secbumeton, simetonand terbumeton; methylthiotriazine herbicides such as ametryn,aziprotryne, cyanatryn, desmetryn, dimethametryn, methoprotryne,prometryn, simetryn and terbutryn; triazinone herbicides such asametridione, amibuzin, hexazinone, isomethiozin, metamitron andmetribuzin; triazole herbicides such as amitrole, cafenstrole, epronazand flupoxam; triazolone herbicides such as amicarbazone, bencarbazone,carfentrazone, flucarbazone, propoxycarbazone, sulfentrazone andthiencarbazone-methyl; triazolopyrimidine herbicides such ascloransulam, diclosulam, florasulam, flumetsulam, metosulam, penoxsulamand pyroxsulam; uracil herbicides such as butafenacil, bromacil,flupropacil, isocil, lenacil and terbacil; 3-phenyluracils; ureaherbicides such as benzthiazuron, cumyluron, cycluron, dichloralurea,diflufenzopyr, isonoruron, isouron, methabenzthiazuron, monisouron andnoruron; phenylurea herbicides such as anisuron, buturon, chlorbromuron,chloreturon, chlorotoluron, chloroxuron, daimuron, difenoxuron,dimefuron, diuron, fenuron, fluometuron, fluothiuron, isoproturon,linuron, methiuron, methyldymron, metobenzuron, metobromuron, metoxuron,monolinuron, monuron, neburon, parafluoron, phenobenzuron, siduron,tetrafluoron and thidiazuron; pyrimidinylsulfonylurea herbicides such asamidosulfuron, azimsulfuron, bensulfuron, chlorimuron, cyclosulfamuron,ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron,foramsulfuron, halosulfuron, imazosulfuron, mesosulfuron, nicosulfuron,orthosulfamuron, oxasulfuron, primisulfuron, pyrazosulfuron,rimsulfuron, sulfometuron, sulfosulfuron and trifloxysulfuron;triazinylsulfonylurea herbicides such as chlorsulfuron, cinosulfuron,ethametsulfuron, iodosulfuron, metsulfuron, prosulfuron, thifensulfuron,triasulfuron, tribenuron, triflusulfuron and tritosulfuron;thiadiazolylurea herbicides such as buthiuron, ethidimuron, tebuthiuron,thiazafluoron and thidiazuron; and unclassified herbicides such asacrolein, allyl alcohol, azafenidin, benazolin, bentazone,benzobicyclon, buthidazole, calcium cyanamide, cambendichlor,chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, cinmethylin,clomazone, CPMF, cresol, ortho-dichlorobenzene, dimepiperate, endothal,fluoromidine, fluridone, fluorochloridone, flurtamone, fluthiacet,indanofan, methazole, methyl isothiocyanate, nipyraclofen, OCH,oxadiargyl, oxadiazon, oxaziclomefone, pentachlorophenol, pentoxazone,phenylmercury acetate, pinoxaden, prosulfalin, pyribenzoxim, pyriftalid,quinoclamine, rhodethanil, sulglycapin, thidiazimin, tridiphane,trimeturon, tripropindan and tritac. The herbicidal compounds of thepresent invention can, further, be used in conjunction with glyphosate,glufosinate or 2,4-D on glyphosate-tolerant, glufosinate-tolerant or2,4-D-tolerant crops. It is generally preferred to use the compounds ofthe invention in combination with herbicides that are selective for thecrop being treated and which complement the spectrum of weeds controlledby these compounds at the application rate employed. It is furthergenerally preferred to apply the compounds of the invention and othercomplementary herbicides at the same time, either as a combinationformulation or as a tank mix.

The compounds of the present invention can generally be employed incombination with known herbicide safeners, such as benoxacor,benthiocarb, brassinolide, cloquintocet (mexyl), cyometrinil, daimuron,dichlormid, dicyclonon, dimepiperate, disulfoton, fenchlorazole-ethyl,fenclorim, flurazole, fluxofenim, furilazole, isoxadifen-ethyl,mefenpyr-diethyl, MG 191, MON 4660, naphthalic anhydride (NA),oxabetrinil, R29148 and N-phenyl-sulfonylbenzoic acid amides, to enhancetheir selectivity. They can additionally be employed to controlundesirable vegetation in many crops that have been made tolerant to orresistant to them or to other herbicides by genetic manipulation or bymutation and selection. For example, corn, wheat, rice, soybean,sugarbeet, cotton, canola, and other crops that have been made tolerantor resistant to compounds that are acetolactate synthase inhibitors insensitive plants can be treated. Many glyphosate and glufosinatetolerant crops can be treated as well, alone or in combination withthese herbicides. Some crops (e.g. cotton) have been made tolerant toauxinic herbicides such as 2,4-dichlorophenoxyacetic acid. Theseherbicides may be used to treat such resistant crops or other auxintolerant crops.

While it is possible to utilize the 6-aryl-4-amino-picolinate compoundsof Formula I directly as herbicides, it is preferable to use them inmixtures containing a herbicidally effective amount of the compoundalong with at least one agriculturally acceptable adjuvant or carrier.Suitable adjuvants or carriers should not be phytotoxic to valuablecrops, particularly at the concentrations employed in applying thecompositions for selective weed control in the presence of crops, andshould not react chemically with the compounds of Formula I or othercomposition ingredients. Such mixtures can be designed for applicationdirectly to weeds or their locus or can be concentrates or formulationsthat are normally diluted with additional carriers and adjuvants beforeapplication. They can be solids, such as, for example, dusts, granules,water dispersible granules, or wettable powders, or liquids, such as,for example, emulsifiable concentrates, solutions, emulsions orsuspensions.

Suitable agricultural adjuvants and carriers that are useful inpreparing the herbicidal mixtures of the invention are well known tothose skilled in the art.

Liquid carriers that can be employed include water, toluene, xylene,petroleum naphtha, crop oil, acetone, methyl ethyl ketone,cyclohexanone, trichloroethylene, perchloroethylene, ethyl acetate, amylacetate, butyl acetate, propylene glycol monomethyl ether and diethyleneglycol monomethyl ether, methanol, ethanol, isopropanol, amyl alcohol,ethylene glycol, propylene glycol, glycerine, and the like. Water isgenerally the carrier of choice for the dilution of concentrates.

Suitable solid carriers include talc, pyrophyllite clay, silica,attapulgus clay, kaolin clay, kieselguhr, chalk, diatomaceous earth,lime, calcium carbonate, bentonite clay, Fuller's earth, cotton seedhulls, wheat flour, soybean flour, pumice, wood flour, walnut shellflour, lignin, and the like.

It is usually desirable to incorporate one or more surface-active agentsinto the compositions of the present invention. Such surface-activeagents are advantageously employed in both solid and liquidcompositions, especially those designed to be diluted with carrierbefore application. The surface-active agents can be anionic, cationicor nonionic in character and can be employed as emulsifying agents,wetting agents, suspending agents, or for other purposes. Typicalsurface-active agents include salts of alkyl sulfates, such asdiethanolammonium lauryl sulfate; alkylarylsulfonate salts, such ascalciumdodecylbenzenesulfonate; alkylphenol-alkylene oxide additionproducts, such as nonylphenol-C₁₋₈ ethoxylate; alcohol-alkylene oxideaddition products, such as tridecyl alcohol-C₁₆ ethoxylate; soaps, suchas sodium stearate; alkylnaphthalenesulfonate salts, such as sodiumdibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts,such as sodium di(2-ethylhexyl) sulfosuccinate; sorbitol esters, such assorbitol oleate; quaternary amines, such as lauryl trimethylammoniumchloride; polyethylene glycol esters of fatty acids, such aspolyethylene glycol stearate; block copolymers of ethylene oxide andpropylene oxide; and salts of mono and dialkyl phosphate esters.

Other adjuvants commonly used in agricultural compositions includecompatibilizing agents, antifoam agents, sequestering agents,neutralizing agents and buffers, corrosion inhibitors, dyes, odorants,spreading agents, penetration aids, sticking agents, dispersing agents,thickening agents, freezing point depressants, antimicrobial agents, andthe like. The compositions may also contain other compatible components,for example, other herbicides, plant growth regulants, fungicides,insecticides, and the like and can be formulated with liquid fertilizersor solid, particulate fertilizer carriers such as ammonium nitrate, ureaand the like.

The concentration of the active ingredients in the herbicidalcompositions of this invention is generally from about 0.001 to about 98percent by weight. Concentrations from about 0.01 to about 90 percent byweight are often employed. In compositions designed to be employed asconcentrates, the active ingredient is generally present in aconcentration from about 5 to about 98 weight percent, preferably about10 to about 90 weight percent. Such compositions are typically dilutedwith an inert carrier, such as water, before application. The dilutedcompositions usually applied to weeds or the locus of weeds generallycontain about 0.0001 to about 1 weight percent active ingredient andpreferably contain about 0.001 to about 0.05 weight percent.

The present compositions can be applied to weeds or their locus by theuse of conventional ground or aerial dusters, sprayers, and granuleapplicators, by addition to irrigation water, and by other conventionalmeans known to those skilled in the art.

The following Examples are presented to illustrate the various aspectsof this invention and should not be construed as limitations to theclaims. Many of the starting materials useful for the preparation of thecompounds of the present invention, e.g.,4-amino-3,6-dichloropyridine-2-carboxylic acid,4-amino-3,5,6-trifluoro-2-cyanopyridine, methyl4-amino-6-bromo-3,5-difluorpyridine-2-carboxylate and methyl4-amino-6-bromo-3-chloropyridine-2-carboxylate, are described in U.S.Pat. No. 6,297,197 B1.

EXAMPLES 1. Preparation of 3-bromo-6-chloro-2-fluorophenol

A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) intetrahydrofuran (THF; 50 mL) was slowly added to lithium diisopropylamide (LDA; 0.125 mol) in THF (600 mL) at −50° C. After addition thesolution was warmed to −20° C. and then cooled to −50° C. and a solutionof trimethyl borate (13.5 g, 0.130 mol) in tetrahydrofuran (20 mL) wasadded slowly and the temperature was warmed to −20° C. The mixture wasthen cooled to −70° C. and solution of peracetic acid (32% in aceticacid, 0.150 mol) was slowly added and the mixture was warmed to ambienttemperature. Water (250 mL) was added and solution extracted with ethylacetate (2×200 mL). The combined organic phases were dried andconcentrated. The black oil was purified by column chromatography (20%ethyl acetate in hexanes) to give 3-bromo-6-chloro-2-fluorophenol (14.1g, 0.063 mol): ¹H NMR (CDCl₃): δ 7.05 (m, 2H), 5.5 (bs, 1H).

The following compounds were prepared according to the procedure ofExample 1.

3-Bromo-2,6-dichlorophenol: mp 69-70° C.

3-Bromo-2-fluoro-6-trifluoromethylphenol: ¹H NMR (CDCl₃): δ 7.20 (m,2H), 5.85 (bs, 1H).

3-Bromo-2-chloro-6-fluorophenol: LC/MS (m/z=225).

2. Preparation of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene

A heterogeneous mixture of 3-bromo-6-chloro-2-fluorophenol (14.4 g,0.064 mol), methyl iodide (13.5 g, 0.096 mol) and potassium carbonate(8.8 g, 0.064 mol) in acetonitrile (100 mL) was heated under reflux for2 hours. The mixture was cooled, diluted with water (100 mL) andextracted with ethyl ether (2×150 mL). The combined extracts were driedand concentrated. The dark oil was purified by chromatography (5% ethylacetate in hexanes) to give 1-bromo-4-chloro-2-fluoro-3-methoxybenzene(14.8 g, 0.062 mol): ¹H NMR (CDCl₃): δ 7.20 (m, 1H), 7.10 (dd, 1H), 4.0(s, 3H).

The following compounds were prepared according to the procedure ofExample 2.

1-Bromo-4-chloro-3-ethoxy-2-fluorobenzene: ¹H NMR (CDCl₃): δ 7.20 (m,1H), 7.10 (dd, 1H), 4.20 (q, 2H), 1.50 (t, 3H).

1-Bromo-4-chloro-2-fluoro-3-isopropropoxybenzene: ¹H NMR (CDCl₃): δ 7.20(m, 1H), 7.10 (dd, 1H), 4.5 (m, 1H), 1.40 (d, 6H).

1-Bromo-4-chloro-2-fluoro-3-(2-methoxyethoxy)benzene: ¹H NMR (CDCl₃): δ7.25 (m, 1H), 7.15 (dd, 1H), 4.25 (t, 2H), 3.75 (t, 2H), 3.5 (s, 3H).

1-Bromo-2-fluoro-3-methoxy-4-trifluoromethylbenzene: ¹H NMR (CDCl₃): δ7.39 (d, 1H), 7.21 (d, 1H), 6.18 (tt, 1H), 4.24 (td, 2H).

1-Bromo-2,4-dichloro-3-ethoxybenzene: ¹H NMR (CDCl₃): δ 7.32 (d, 1H),7.17 (d, 1H), 4.10 (q, 2H), 1.47 (t, 3H).

1-Bromo-2,4-dichloro-3-methoxybenzene: ¹H NMR (CDCl₃): δ 7.35 (d, 1H),7.15 (d, 1H), 3.95 (s, 3H).

1-Chloro-3,5-difluoro-2-methoxybenzene: GC-MS (m/z=178).

1-Chloro-3,5-difluoro-2-ethoxybenzene: GC-MS (m/z=192) bp 80-85°/30 mm.

1,3-Dichloro-5-fluoro-2-methoxybenzene: GC-MS (m/z=194).

1-Bromo-3-butoxy-4-chloro-2-fluorobenzene: GC-PCI (m/z=180).

1-Bromo-4-chloro-2-fluoro-3-methoxymethoxybenzene: GC-MS (m/z=269).

1-Bromo-2-chloro-4-fluoro-3-methoxybenzene: GC-MS (m/z=239).

3-Chloro-5-fluoro-2-methoxybenzaldehyde: GC-MS (m/z=188).

1,3-Difluoro-3-ethoxybenzene: GC-MS (m/z=158).

3. Preparation of 1-bromo-4-chloro-2-fluoro-5-methoxybenzene

A solution of 4-chloro-2-fluoro-5-methoxyaniline (25.0 g, 0.143 mol) in10% HBr (250 mL) was cooled to 0° C. and a solution of sodium nitrite(15.0 g, 0.218 mol) in water (20 mL) was slowly added. Methylenechloride (50 mL) and curpric bromide (30.0 g, 0.244 mol) were addedslowly and then the mixture was warmed to ambient temperature andstirred for 1 hour. The reaction mixture was filtered through a bed ofcelite and extracted with methylene chloride (2×100 mL) and the combinedorganic phases were dried (sodium sulfate) and concentrated.Chromatography of the dark oil (5% ethyl acetate in hexanes) gave1-bromo-4-chloro-2-fluoro-5-methoxybenzene (16.6 g, 0.070 mol): ¹H NMR(CDCl₃): δ 7.20 (m, 1H) 7.05 (dd, 1H), 4.00 (s, 3H).

4. Preparation of 1-bromo-4-chloro-2-fluoro-3-difluoromethoxybenzene

To a solution of 3-bromo-6-chloro-2-fluorophenol (1.00 g, 4.44 mmol) andsodium chlorodifluoroacetate in dimethylformamide (DMF; 9 mL) was addedpotassium carbonate (1.22 g, 5.32 mmol) and water (1.77 mL) and theresulting mixture heated to 100° C. for 4 hours. The solution was cooledto ambient temperature and concentrated hydrochloric acid (2.5 mL) andwater (4 mL) were added and stirred at ambient temperature overnight.The solution was cooled in an ice bath and neutralized with 2N sodiumhydroxide and then extracted with ethyl ether (2×25 mL). The combinedextracts were washed with brine, dried (sodium sulfate), andconcentrated to give 1-bromo-4-chloro-2-fluoro-3-difluoromethoxybenzene(1.20 g, 4.2 mmol). This material was used without further purification.

5. Preparation of1-bromo-4-chloro-3-(2,2-difluoroethoxy)-2-fluorobenzene

A solution of 3-bromo-6-chloro-2-fluorophenol (15.4 g, 0.068 mol) in DMF(25 mL) was slowly added to a suspension of sodium hydride (60%dispersion in mineral oil) (4.0 g, 0.10 mol) in DMF (100 mL) and themixture was stirred 1 hour. A solution of methanesulfonic acid 2,2difluoroethyl ester (17.5 g, 0.109 mol) in DMF (10 mL) was slowly added.The resulting solution was heated to 70° C. for 18 hours. The solutionwas diluted with water (200 mL) and extracted with ethyl ether. Thecombined organic phases were dried (sodium sulfate) and concentrated.The residual oil was purified by chromatography (in hexanes) to give1-bromo-4-chloro-3-(2,2-difluoroethoxy)-2-fluorobenzene (9.0 g, 0.031mol): ¹H NMR (CDCl₃): δ 7.3 (m, 1H), 7.10 (dd, 1H), 6.15 (dt, 1H), 4.35(m, 2H).

The following compound was prepared according to the procedure ofExample 5.

1-Bromo-2,4-dichloro-3-(2,2-difluoroethoxy)benzene: ¹H NMR (CDCl₃): δ7.35 (m, 1H), 7.15 (dd, 1H), 6.15 (tt, 1H), 4.35 (dt, 2H).

6. Preparation of 1-bromo-4-chloro-2-fluoro-3-(methylthio)benzene

A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) inTHF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL) at −50°C. After addition, the solution was warmed to −20° C. and then cooled to−50° C. and a solution of dimethyldisulfide (18.8 g, 0.20 mol) in THF(50 mL) was slowly added and the mixture was warmed to ambienttemperature. The reaction was quenched with water (200 mL) and extractedwith ethyl acetate (2×150 mL) and the combined organic phases dried(sodium sulfate) and concentrated. The residual red oil was purified bychromatography (5% ethyl acetate in hexanes) to give1-bromo-4-chloro-2-fluoro-3-(methylthio)benzene (23.9 g, 0.094 mol): ¹HNMR (CDCl₃): δ 7.40 (m, 1H), 7.15 (dd, 1H), 2.50 (s, 3H).

The following compound was prepared according to the procedure ofExample 6.

1-Bromo-2,4-dichloro-3-(methylthio)benzene: ¹H NMR (CDCl₃): δ 7.52 (d,1H), 7.25 (d, 1H), 2.46 (s, 3H).

7. Preparation of 3-bromo-6-chloro-2-fluorobenzaldehyde

A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) inTHF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL) at −50°C. After addition the solution was warmed to −20° C. and then cooled to−50° C. and a solution of DMF (14.6 g, 0.20 mol) in THF (50 mL) wasslowly added and the reaction mixture was warmed to ambient temperature.The reaction was quenched with water (250 mL) and extracted with ethylacetate (2×150 mL) and the combined organic phases were dried (sodiumsulfate) and concentrated. The solid residue was recrystallized fromhexane to give 3-bromo-6-chloro-2-fluorobenzaldehyde (40.0 g, 0.169mol): mp 92-93° C.

The following compounds were prepared according the procedure of Example7 by quenching with appropriate electrophile, e.g., an aldehyde, esteror ketone.

1-(3-Bromo-6-chloro-2-fluorophenyl)-1-ethanol): ¹H NMR (CDCl₃): δ 7.40(m, 1H), 7.15 (m, 1H), 5.40 (m, 1H), 2.50 (m, 1H), 1.85 (d, 3H).

3-Bromo-2,4-dichlorobenzaldehyde: mp 96-97° C.

1-(3-Bromo-2,6-dichlorophenyl)-1-ethanol): ¹H NMR (CDCl₃): δ 7.60 (d,1H), 7.15 (d, 1H), 5.45 (m, 1H), 3.0 (d, 1H), 1.85 (d, 3H).

1-Bromo-4-chloro-3-ethyl-2-fluorobenzene: GC/PCI (m/z=236).

1-(3-Bromo-6-chloro-2-fluorophenyl)-2,2,2-trifluoroethanone: GC/PCI(m/z=304).

1-(3-Bromo-6-chloro-2-fluorophenyl)-1-propanol): ¹H NMR (CDCl₃): δ 7.40(m, 1H), 7.15 (m, 1H), 5.40 (m, 1H), 2.50 (m, 1H), 1.90 (m, 4H), 1.00(t, 3H).

2-(3-Bromo-6-chloro-2-fluorophenyl)-2-propanol): ¹H NMR (CDCl₃): δ 7.40(m, 1H), 7.15 (m, 1H), 3.45 (s, 1H), 1.80 (m, 6H).

8. Preparation of 3-chloro-5-fluoro-2-hydroxybenzaldehyde

A solution of 2-chloro-4-fluorophenol (15.0 g, 102 mmol) in 150 g of 50%sodium hydroxide, water (30 mL) and chloroform (45 mL) were heated underreflux for 8 hours, additional chloroform (45 mL) was added every 2hours. The mixture was then cooled and allowed to stand for 18 hours andthe precipitated sodium salt was collected. The solid was slurried inwater (200 mL) and the pH adjusted to 1.5 with 6N hydrochloric acid andthen extracted with ethyl acetate (2×100 mL). The combined extracts werewashed with brine, dried and concentrated. The residue was purified bychromatography (1:1 methylene chloride:hexanes) to give3-chloro-5-fluoro-2-hydroxybenzaldehyde (5.0 g, 29 mmol): LC/MS(m/z=174).

9. Preparation of 1-bromo-4-chloro-2-fluoro-3-difluoromethylbenzene

Diethylamino sulfur trifluoride (15.3 g, 0.096 mol) was added slowly toa solution of 3-bromo-6-chloro-2-fluorobenzaldehyde (7.50 g, 0.032 mol)in methylene chloride at 0° C. and the mixture stirred for 1 hour afterallowing to warm to ambient temperature. The reaction was carefullyquenched with a saturated solution of sodium bicarbonate in water (100mL) and extracted with methylene chloride (2×75 mL) and the combinedextracts dried (sodium sulfate) and concentrated to give1-bromo-4-chloro-2-fluoro-3-difluoromethylbenzene (7.20 g, 0.028 mol):¹H NMR (CDCl₃): δ 7.60 (m, 1H), 7.05 (m, 1H), 7.00 (d, 1H).

The following compounds were prepared according to the procedure inExample 9.

1-Bromo-2,4-dichloro-3-difluoromethylbenzene: LC/MS ESI (m/z=271).

1-Difluoromethyl-3-fluoro-4-iodo-2-methoxybenzene: LC/MS (m/z=302).

2-Chloro-4-difluoromethyl-3-methoxy-1-nitrobenzene: LC/MS (m/z=237)(used without complete purification.

3-Chloro-1-difluoromethyl-2-methoxybenzene: LC/MS (m/z=210).

10. Preparation of 2-chloro-4-difluoromethyl-3-methoxyaniline

A solution of crude 2-chloro-4-difluoromethyl-3-methoxy-1-nitrobenzenein ethanol (50 mL) containing 5% palladium on charcoal (250 mg) washydrogenated (50 psi) for 5 hours. The solution was filtered andconcentrated to give 2-chloro-4-difluoromethyl-3-methoxyaniline (1.3 g,48 mmol): LC/MS (m/z=207).

11. Preparation of N-pivaloyl-2-bromo-4-chloro-3-methoxyaniline

To solution of N-pivaloyl-4-chloro-3-methoxyaniline (5.0 g, 21 mmol) intetrahydrofuran (60 mL) at −60° C. was added n-butyl lithium (2.5M, 44mmol). The solution was allowed to warm to 0° C. and stir for 3 hours.Ethylene dibromide (9.9 g, 53 mmol) was added and the solution stirredfor 18 hours before being quenched with ammonium chloride (saturatedsolution, 20 mL) and extracted with ethyl ether (2×50 mL). The combinedextracts were washed with brine, dried (sodium sulfate) andconcentrated. The residue was purified by chromatography (10% ethylacetate/hexanes) to give N-pivaloyl-2-bromo-4-chloro-3-methoxyaniline(3.7 g, 1.2 mmol): LC/MS (m/z=320).

12. Preparation of 2-bromo-4-chloro-1-iodo-3-methoxybenzene

A solution of N-pivaloyl-2-bromo-4-chloro-3-methoxyaniline (3.7 g, 1.2mmol) in dioxane (35 mL) was treated with concentrated hydrochloric acid(35 mL) and the solution heated under reflux for 2 hours. After thesolution was cooled the pH was adjusted to 10 by addition of sodiumhydroxide (50% solution) and extracted with ethyl ether (2×50 mL). Thecombined extracts were washed with brine, dried (sodium sulfate) andconcentrated. The crude aniline was dissolved in 2N hydrochloric acidand sodium nitrite (750 mg, 111 mmol) was added and the solution stirredfor 20 minutes. This solution was poured into a vigorously stirredsolution of sodium iodide (3.3 g, 22 mmol) in water (20 mL) andmethylene chloride (30 mL) and stirred for 20 minutes. The solution wasthen extracted with methylene chloride (2×25 mL) and the combinedextracts washed with brine, dried (sodium sulfate) and concentrated. Theresidue was purified by chromatography (hexanes) to give2-bromo-4-chloro-1-iodo-3-methoxybenzene (1.5 g, 0.6 mmol): LC/MS(m/z=267).

The following compounds were prepared according to the procedure ofExample 12.

4-Chloro-2,6-difluoro-5-methyl-1-iodobenzene: bp 60-70° C./0.75 mm.

2-Chloro-4-difluoromethyl-3-methoxy-1-iodobenzene: LC/MS (m/z=318).

1-chloro-2-difluoromethyl-3,5-difluoro-4-iodobenzene: LC/MS (m/z=324).

13. Preparation of 3-chloro-2-methoxy-4-nitrotoluene

A solution of 4-nitro-2-hydroxytoluene (5.0 g, 33 mmol) in chloroform(40 mL) was heated under reflux and treated with a stream of chlorinefor 1 hour. Upon cooling, the solution was washed with sodiumbicarbonate (saturated solution), brine, dried (sodium sulfate) andconcentrated. The residue was dissolved in acetonitrile (75 mL), treatedwith potassium carbonate (9.1 g, 66 mmol) and iodomethane (2.5 ml, 5.7g, 40 mmol) and heated under reflux for 2 hours. Upon cooling, thesolution was concentrated and the residue was taken up in ethyl ether(75 mL) and washed with water (50 mL), brine, dried (sodium sulfate) andconcentrated. The crude product was purified by chromatography on silicawith 1-5% ethyl acetate/hexane to 3-chloro-2-methoxy-4-nitrotoluene (3.0g, 15 mmol): LC/MS (m/z=201).

14. Preparation of 3-chloro-2-methoxy-4-nitrobenzaldehyde

A solution of 3-chloro-2-methoxy-4-nitrotoluene (1.0 g, 5.0 mmol) inacetic acid (10 mL) and acetic anhydride (10 mL) was cooled to 5° C. andtreated with 1 mL conc. H₂SO₄. Chromium trioxide (1.4 g, 14 mmol) wasadded in portions over 10 minutes while the reaction temperature wasmaintained at 0-5° C. After 30 minutes at this temperature, the mixturewas poured onto ice-water (20 g) and the mixture was extracted withethyl aetate (2×25 mL). The combined organic phases were washed withbrine, dried (sodium sulfate) and concentrated. The crude bis-acetatewas combined with water (10 mL), ethanol (10 mL) and concentratedsulfuric acid (1 mL) and heated to reflux for 40 minutes. Upon cooling,the mixture was diluted with water (20 mL) and extracted with ethylacetate (2×50 mL). The combined extracts were washed with brine, dried(sodium sulfate) and concentrated. The crude mixture was chromatographed(10% ethyl acetate/hexanes) to give3-chloro-2-methoxy-4-nitrobenzaldehyde (400 mg, 1.9 mmol): LC/MS(m/z=215).

15. Preparation of (3-bromo-6-chloro-2-fluorophenyl)methanol

To a solution of 3-bromo-6-chloro-2-fluorobenzaldehyde (20.0 g, 0.084mol) in ethanol (250 mL) was added sodium borohydride (6.4 g, 0.168 mol)and the reaction mixture was stirred at ambient temperature for 1 hour.The mixture was diluted with water (300 mL) and extracted with ethylacetate (2×200 mL), dried (sodium sulfate) and concentrated. The crudesolid was recrystallized from hexanes to give(3-bromo-6-chloro-2-fluorophenyl)methanol (10.4 g, 0.043 mol): ¹H NMR(CDCl₃): δ 7.50 (m, 1H), 7.15 (dt, 1H), 4.90 (s, 2H), 2.10 (bs, 1H).

The following compounds were prepared according to the procedure ofExample 15.

1-(3-Bromo-6-chloro-2-fluorophenyl)-2,2,2-trifluoroethanol: GC/PCI(m/z=306).

3-Fluoro-4-iodo-2-methoxyphenyl)methanol: LC/MS (m/z=282).

16. Preparation of 1-bromo-4-chloro-3-fluoromethyl-2-fluorobenzene

A solution of diethylamino sulfur trifluoride (7.6 g, 0.047 mol) inmethylene chloride (25 mL) was slowly added to(3-bromo-6-chloro-2-fluorophenyl)methanol (10.3 g, 0.043 mol) inmethylene chloride (150 mL) at 0° C. The solution was stirred at ambienttemperature for 1 hour. A saturated solution of sodium bicarbonate (100mL) was cautiously added and the mixture extracted with methylenechloride (2×100 mL). The combined organic phases were dried (sodiumsulfate) and concentrated. The dark residual oil was purified bychromatography (5% ethyl acetate in hexanes) to give1-bromo-4-chloro-3-fluoromethyl-2-fluorobenzene (6.20 g, 0.024 mol): ¹HNMR (CDCl₃): δ 7.55 (m, 1H) 7.18 (dd, 1H) 5.6 (d, 2H).

The following compounds were prepared according to the procedure inExample 16.

1-Bromo-4-chloro-2-fluoro-3-(1-fluoro-1-methylethyl)benzene: ¹H NMR(CDCl₃): δ 7.42 (m, 1H), 7.10 (m, 1H), 6.05 (dq, 1H) 1.95 (dd, 6H).

1-Bromo-2,4-dichloro-3-(1-fluoroethyl)benzene: GC/PCI (m/z=270).

1-Bromo-4-chloro-2-fluoro-3-(1-fluoroethyl)benzene: GC/PCI (m/z=255).

1-Bromo-4-chloro-2-fluoro-3-(1,2,2,2-tetrafluoroethyl)benzene: GC/EI(m/z=308).

1-Bromo-4-chloro-2-fluoro-3-(1-fluoropropyl)benzene: GC/EI (m/z=267).

2-Fluoro-4-fluoromethyl-1-iodo-3-methoxybenzene: LC/MS (m/z=284).

17. Preparation of 1-bromo-4-chloro-2-fluoro-3-methoxymethylbenzene

A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) inTHF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL) at −50°C. After addition the solution was warmed to −20° C. and then cooled to−50° C. a solution of bromomethoxymethane (25 g, 0.200 mol) in THF (25mL) was slowly added and the reaction mixture was warmed to ambienttemperature. The reaction was quenched with water (400 mL) and extractedwith diethyl ether (2×150 mL). The combined organic phases were dried(sodium sulfate) and concentrated. The residual oil was distilled(70°-75° C./0.5 mm) to give1-bromo-4-chloro-2-fluoro-3-methoxymethylbenzene (18.0 g, 0.071 mol): ¹HNMR (CDCl₃): δ 7.50 (m, 1H), 7.15 (dd, 1H), 4.65 (s, 1H), 3.40 (s, 1H).

The following compound was prepared according to the procedure ofExample 17.

1-Bromo-4-chloro-2-fluoro-3-methylbenzene: ¹H NMR (CDCl₃): δ 7.30 (m,1H), 7.05 (dd, 1H), 2.35 (s, 3H).

18. Preparation of2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane

To a solution of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (10.4 g,0.043 mol) in diethyl ether (150 mL) at −78° C. was slowly added n-butyllithium (2.5M, 19.0 mL, 0.0475 mol) and the solution was stirred for 30minutes. A solution of triisopropyl borate (12.0 g, 0.064 ml) in THF (25mL) was slowly added and the solution was warmed to a 0° C. Acetylchloride (10.0 g, 0.13 mol) was added. After stirring for 1 hour, thesolution was concentrated and the solid residue taken into ethyl acetate(150 mL) and a 1N solution of sodium hydroxide (50 mL). Ice was added tothe aqueous phase which was then acidified with sufficient concentratedhydrochloric acid to obtain a pH of 2. The heterogeneous mixture wasextracted with ethyl acetate (2×150 mL) and the combined organic phasesdried (sodium sulfate) and concentrated. The resulting solid wasslurried in toluene and propane-1,3-diol (6.6 g, 0.09 mol) was added andthe mixture heated under reflux with water being removed with aDean-Stark trap. After 2 hours the mixture was cooled and concentrated.The resulting oil was taken into methylene chloride (50 mL) and washedwith water (25 mL), then dried (sodium sulfate) and concentrated to give2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (6.4 g,0.062 mol): ¹H NMR (CDCl₃): δ 7.15 (m, 1H), 6.95 (dd, 1H), 4.05 (t, 4H),3.8 (s, 3H), 1.95 (t, 2H).

The following compounds were prepared according to the procedure ofExample 18.

2-(4-Chloro-2-fluoro-5-methoxyphenyl)-[1,3,2]-dioxaborinane: ¹H NMR(CDCl₃): δ 7.25 (d, 1H), 7.05 (d, 1H), 4.20 (t, 4H), 4.15 (s, 3H), 2.10(t, 2H).

2-(4-Chloro-2-fluoro-3-ethoxyphenyl)-[1,3,2]-dioxaborinane: ¹H NMR(CDCl₃): δ 7.30 (m, 1H), 7.05 (dd, 1H), 4.20 (m, 7H), 2.05 (t, 3H), 1.50(t, 3H).

2-(4-Chloro-2-fluoro-3-(methylthio)phenyl)-[1,3,2]-dioxaborinane: ¹H NMR(CDCl₃): δ 7.50 (m, 1H), 7.18 (dd, 1H), 4.20 (t, 4H), 2.50 (s, 3H), 2.05(t, 2H).

2-(4-Chloro-2-fluoro-3-methoxymethylphenyl)-[1,3,2]-dioxaborinane: ¹HNMR (CDCl₃): δ 7.6 (dt, 1H), 7.25 (dd, 1H), 4.76 (s, 2H), 4.20 (t, 4H),3.40 (s, 3H), 2.05 (t, 2H).

2-(4-Chloro-2-fluoro-3-isopropoxyphenyl)-[1,3,2]-dioxaborinane: ¹H NMR(CDCl₃): δ 7.25 (m, 1H), 7.15 (dd, 1H), 4.5 (q, 1H), 4.20 (t, 4H), 2.05(t, 2H), 1.50 (d, 6H).

2-(4-Chloro-2-fluoro-3-difluoromethylphenyl)-[1,3,2]-dioxaborinane ¹HNMR (CDCl₃): δ 7.75 (m, 1H), 7.15 (dd, 1H), 6.90-7.15 (t, 1H) 4.20 (t,4H), 2.05 (t, 2H).

2-(4-Chloro-2-fluoro-3-fluoromethylphenyl)-[1,3,2]-dioxaborinane ¹H NMR(CDCl₃): δ 7.70 (m, 1H), 7.25 (dd, 1H), 5.8 (d, 2H), 4.20 (t, 4H), 2.05(t, 2H).

4-[1,3,2]-Dioxaborinan-2-yl-3-fluoro-2-methoxybenzonitrile: ¹H NMR(CDCl₃): δ 7.40 (m, 1H), 7.3 (dd, 1H), 4.25 (t, 4H), 4.15 (s, 3H), 2.10(t, 3H).

2-(4-Chloro-2-fluoro-3-methoxyethoxyphenyl)-[1,3,2]-dioxaborinane: ¹HNMR (CDCl₃): δ 7.35 (m, 1H), 7.15 (dd, 1H), 4.25 (m, 6H), 3.75 (d, 2H),3.48 (s, 3H), 2.15 (t, 3H).

2-(2,4-Dichloro-3-ethoxyphenyl)-[1,3,2]-dioxaborinane: ¹H NMR (DMSO-d₆):δ 7.40 (d, 1H), 7.29 (d, 1H), 4.08 (m, 4H), 4.00 (q, 2H), 1.99 (m, 2H),1.34 (t, 3H).

2-[4-Chloro-2-fluoro-3-(2,2-difluoroethoxyphenyl]-[1,3,2]-dioxaborinane:¹H NMR (CDCl₃): δ 7.45 (m, 1H), 7.15 (dd, 1H), 6.15 (tt, 1H), 4.38 (t,4H), 4.20 (t, 2H), 2.10 (t, 2H).

2-(4-Chloro-2-fluoro-5-ethoxyphenyl)-[1,3,2]-dioxaborinane: ¹H NMR(CDCl₃): δ 7.25 (d, 1H), 7.05 (d, 1H), 4.20 (t, 4H), 4.15 (t, 2H), 2.10(t, 2H), 1.45 (t, 3H).

2-(2,4-Dichloro-3-(methylthio)phenyl)-[1,3,2]-dioxaborinane: ¹H NMR(CDCl₃): δ 7.45-7.28 (m, 2H), 3.86 (m, 4H), 2.42 (s, 3H), 1.80 (m, 2H).

6-Chloro-3-[1,3,2]-dioxaborinan-2-yl-2-fluorobenzonitrile: ¹H NMR(CDCl₃): δ 7.85 (m, 1H), 6.25 (m, 1H), 4.20 (m, 4H), 2.10 (m, 2H).

19. Preparation of 1-fluoro-2,3-methylenedioxybenzene

Alliquat 336 (methyltrioctylammonium chloride, 0.63 g, 1.6 mmol),dibromomethane (40.7 g, 234.2 mmol) and water (31 mL) were placed in a500 mL 3-necked flask equipped with an addition funnel, condenser and astir bar. The addition funnel was charged with a solution of3-fluorocatechol (20.0 g, 160 mmol) in 5M sodium hydroxide (80 mL). Themixture in the flask was heated to reflux and the solution of thecatechol was added dropwise with good stirring over 2 hours and theresulting dark mixture heated an additional 2 hours at reflux. Aftercooling to room temperature, the reaction was diluted with methylenechloride and the layers separated. The aqueous layer was extracted withmethylene chloride and the combined organic layers dried (Na₂SO₄ withcharcoal). Filtration and concentration to a constant weight on therota-vap gave 1-fluoro-2,3-methylenedioxybenzene (14.6 g, 104.2 mmol) asa dark yellow oil: ¹H NMR (CDCl₃); 6.80 (m, 1H), 6.68 (m, 2H), 6.04 (s,2H).

20. Preparation of 2-fluoro-3,4-methylenedioxyphenylboronic acid

1-Fluoro-2,3-methylenedioxybenzene (5.0 g, 35.7 mmol) was dissolved inTHF (70 mL) and the solution cooled to −65° C. in a dry ice acetonebath. n-Butyl lithium (2.5 g, 15.7 mL, 39.3 mmol) was added to thesolution via syringe with stirring. The reaction was allowed to warm to−35° C. over 1 hour then re-cooled to −65° C. and treated withtrimethylborate (4.1 g, 39.3 mmol) via syringe. The reaction was allowedto warm slowly to room temperature then quenched with 1N HCl (50 mL),stirred for 15 minutes then diluted with ether and the layers separated.The organic layer was extracted with 1N sodium hydroxide and thisextract separated from the ether and acidified with 1N hydrochloricacid. The acidic aqueous layer was extracted with two portions of etherand these combined ether extracts were dried (sodium sulfate), filteredand concentrated to a oily solid which was triturated with methylenedichloride. The resulting solid was collected by filtration, washed withmethylene dichloride and dried to give1-fluoro-2,3-methylenedioxyphenylboronic acid (1.4 g, 7.6 mmol) as a tansolid: ¹H NMR (DMSO-d₆): δ 8.05 (bs, 2H), 7.08 (dd, 1H), 6.76 (d, 1H),6.08 (s, 2H).

The following compounds were prepared according to the procedure inExample 20.

2-Fluoro-3-methoxy-4-methylphenylboronic acid: ¹H NMR (300 MHz,d6-DMSO+H₂O): δ 7.32 (bs, 2H), 7.11 (dd, 1H, J=7.2, 5.7 Hz), 6.92 (d,1H, J=7.2 Hz), 3.74 (s, 3H), 2.19 (s, 3H).

4-Bromo-2-fluoro-3-methoxyphenylboronic acid: ¹H NMR (300 MHz, DMSOd6+D₂O): δ 8.36 (bs, 2H), 7.38 (dd, 1H, J=8.4), 7.17 (dd, 1H), 3.82 (d,3H).

21. Preparation of2-(2-fluoro-3,4-methylenedioxyphenyl)-[1,3,2]-dioxaborinane

2-Fluoro-3,4-methylenedioxyphenylboronic acid (1.4 g, 7.6 mmol) wasslurried in toluene and propane-1,3-diol (0.6 g, 7.9 mmol) and themixture heated under reflux for 0.5 hour. The mixture was cooled,filtered through glass wool and concentrated to give2-(2-fluoro-3,4-methylenedioxyphenyl)-[1,3,2]-dioxaborinane (1.6 g, 7.1mmol): ¹H NMR (DMSO-d₆): δ 7.12 (dd, 1H, J=7.8, 5.7 Hz), 6.75 (d, 1H),6.09 (s, 2H), 4.06 (t, 4H), 1.98 (m, 2H).

22. Preparation of 3-bromo-6-chloro-2-fluorobenzonitrile

A suspension of 3-bromo-6-chloro-2-fluorobenzaldehyde (9.0 g, 0.04 mol)and O-sulfinic acid hydroxyamine (7.50 g, 0.07 mole) in water (300 mL)was warmed to 50° C. for 18 hours. The suspension was cooled and thesolid collected to give 3-bromo-6-chloro-2-fluorobenzonitrile (8.8 g,0.04 mol): ¹H NMR (CDCl₃): δ 7.75 (m, 1H), 7.25 (m, 1H).

23. Preparation of 3-bromo-2-fluoro-6-chlorobenzamide

Concentrated sulfuric acid (15 mL) was placed in a 100 mL 3-neck flaskequipped with an internal thermometer and then heated to 55° C.3-Bromo-2-fluoro-6-chlorobenzonitrile (11.0 g, 47 mmol) was addedportion-wise to the acid with stirring maintaining the temperature above50° C. The dark solution was heated at 65° C. for 24 hours then cooledto room temperature and poured over ice and cautiously neutralized withconcentrated ammonium hydroxide. The mixture was extracted with twoportions of ethyl acetate and the combined organic layers dried overNa₂SO₄ (with charcoal). Filtration and concentration gave3-bromo-2-fluoro-6-chlorobenzamide (11.5 g, 45.5 mmol) as a light orangesolid: mp 157-158° C., ¹H NMR (CDCl₃): δ 7.54 (t, 1H), 7.14 (dd, 1H),6.03 (bs, 1H) 5.81 (bs, 1H).

24. Preparation of 3-bromo-2,6-dichlorobenzamide

3-Bromo-2,6-dichlorobenzoic acid (7.2 g, 26.7 mmol) was treated withthionyl chloride (30 mL, 400.0 mmol) in a 250 mL round bottom flask andthe mixture was heated to reflux for 1 hour then cooled to roomtemperature. Approximately one third of the light yellow solution wasremoved and concentrated in vacuo. The residue was dissolved in THF (16mL) and treated with concentrated ammonium hydroxide (6 mL) with goodstirring. The mixture was partitioned between ethyl acetate andsaturated NaHCO₃ and the layers separated and the organics dried overNa₂SO₄. Filtration and concentration gave 3-Bromo-2,6-dichlorobenzamide(2.19 g) as a foam: mp 117-119° C., ¹H NMR (300 MHz, d6-DMSO): δ 8.10(bs, 1H), 7.88 (bs, 1H), 7.79 (d, 1H, J=8), 7.44 (d, 1H).

25. Preparation of 3-bromo-6-chloro-2-fluoroaniline

Sodium hydroxide (4.0 g, 100.0 mmol) was dissolved in water (70 mL) in a250 mL round bottomed flask and the resulting solution cooled in an icebath and treated with bromine (4.7 g, 29.7 mmol) to give a yellowsolution. 3-Bromo-2-fluoro-6-chlorobenzenecarboxamide (5.0 g, 19.9 mmol)was added as a solid, slowly with good stirring and the orange mixturewas heated to reflux for 2 hours. The cooled reaction mixture wasdiluted with methylene dichloride and the layers separated and themethylene dichloride dried (Na₂SO₄). Crystallization of the concentratedfiltrate from cold hexanes gave 3-bromo-6-chloro-2-fluoroaniline (2.8 g,12.6 mmol) as a off white solid: mp 61-62° C., ¹H NMR (CDCl₃): δ 6.94(dd, 1H), 6.83 (dd, 1H), 4.16 (bs, 2H).

The following compound was prepared according to the procedure inExample 25.

3-Bromo-2,6-dichloroaniline: mp 71-72° C.

26. Preparation of N-(3-bromo-6-chloro-2-fluorophenyl)-N,N-dimethylamine

3-Bromo-6-chloro-2-fluoroaniline (2.5 g, 11.1 mmol) was dissolved in THF(25 mL) in a nitrogen flushed 250 mL round bottomed flask and treatedwith 37% formaldehyde (0.84 g, 2.1 mL, 27.8 mmol), dibutyl tindichloride (0.07 g, 0.22 mmol) and phenyl silane (1.33 g, 12.3 mmol) andallowed to stir at room temperature under nitrogen for 48 hours. Thereaction mixture was concentrated in vacuo and purified by flash silicagel chromatography (hexanes) to giveN-(3-bromo-6-chloro-2-fluorophenyl)-N,N-dimethylamine (2.0 g 7.9 mmol)as a oil: ¹H NMR (CDCl₃): δ 7.19 (dd, 1H), 7.04 (dd, 1H), 2.88 (s, 3H),2.87 (s, 3H).

The following compounds were prepared according to the procedure ofExample 26.

N-(3-Bromo-6-chloro-2-fluorophenyl)-N,N-diethylamine: ¹H NMR (300 MHz,CDCl₃): δ 7.24 (dd, 1H), 7.07 (dd, 1H), 3.16 (dd, 4H), 1.01 (t, 6H)).

N-(3-Bromo-2,6-dichlorophenyl)-N,N-dimethylamine: ¹H NMR (300 MHz,CDCl₃): δ 7.33 (d, 1H), 7.13 (d, 1H), 2.88 (s, 6H).

N-(2-Chloro-4,6-difluorophenyl)-N,N-dimethylamine: Colorless oil. ¹H NMR(300 MHz, CDCl₃): δ 6.93 (ddd, 1H), 6.73 (m, 1H), 2.82 (d, 6H).

27. Preparation of N-(3-bromo-2-fluorophenyl), N-methyl amine

3-Bromo-6-chloro-2-fluoroaniline (1.2 g, 5.2 mmol) was dissolved in THF(12 mL) in a 100 mL round bottomed flask and treated with tetra-N-butylammonium bromide (0.015 g, 0.05 mmol) and powdered sodium hydroxide(0.83 g, 20.9 mmol) with stirring. After 5 minutes, the dark mixture wastreated with dimethyl sulfate (1.3 g, 10.4 mmol) and the mixture heatedat 60° C. for 2 hours. Analysis by TLC (hexanes:ethyl acetate/20:1)indicated some starting material remained. Added additional dimethylsulfate (0.66 g, 5.2 mmol) and continued heating for 1.5 hour thenstirred at room temperature overnight. The reaction was partitionedbetween diethyl ether and water and the layers separated and the aqueousphase extracted with ether. The combined ether layers were washed withwater and dried (MgSO₄). Filtration, concentration and purification byflash silica gel chromatography (hexanes) gaveN-(3-bromo-6-chloro-2-fluorophenyl)-N-methylamine (0.81 g) as acolorless oil: ¹H NMR (300 MHz, CDCl₃): δ 6.93 (dd, 1H, J=8.4), 6.83(dd, 1H), 4.00 (bs, 1H), 3.09 (d, 3H).

28. Preparation of 1,3-difluoro-2-iodo-4-methoxy-5-methylbenzene

A solution of 1,5-difluoro-2-methoxy-3-methylbenzene (0.65 g, 4.1 mmol)in THF (1 mL) was added to LDA (4.3 mmol) in THF (10 mL) at −55° C. andthe solution stirred for 45 minutes. Solid iodine (1.15 g, 4.5 mmol) wasadded and the solution allowed to warm to ambient temperature. Thesolution was diluted with ethyl acetate and washed with sodiumbicarbonate (saturated solution 15 mL) and sodium thiosulfate (saturatedsolution, 15 mL), dried (sodium sulfate) and concentrated. The residuewas purified by chromatography (hexanes) to give1,3-difluoro-2-iodo-4-methoxy-5-methylbenzene: ¹H NMR (300 MHz, CDCl₃):δ 6.72 (dd, 1H), 3.84 (d, 3H), 2.26 (s, 3H).

The following compounds were prepared according to the procedure ofExample 28.

3,5-Difluoro-4-iodo-2-methoxybenzonitrile: mp 106-110° C.

N-(6-Chloro-2,4-difluoro-3-iodophenyl)-N,N-dimethylamine: ¹H NMR (300MHz, CDCl₃): δ 6.98 (dd, 1H), 2.82 (d, 6H).

1,3-Dichloro-5-fluoro-4-iodo-2-methoxybenzene: GC-MS (m/z=320).

1,3-Difluoro-2-iodo-4-methoxy-5-methylbenzene: ¹H NMR (CDCl₃): δ 6.72(dd, 1H), 3.84 (d, 3H), 2.26 (s, 3H).

2,3-Difluoro-4-iodo-benzonitrile: LC/MS (m/z=265).

3-Chloro-1-difluoromethyl-5-fluoro-4-iodo-2-methoxybenzene: LC/MS(m/z=336).

2-Ethoxy-1,3-difluoro-4-iodobenzene: GC-MS (m/z=284).

1,3-Difluoro-2-iodo-4-methoxy-5-methylbenzene: ¹H NMR (CDCl₃): δ 6.72(dd, 1H), 3.84 (d, 3H), 2.26 (s, 3H).

3,5 Difluoro-4-iodo-2-methoxybenzonitrile: mp. 106-110° C.

(6-Chloro-2,4-difluoro-3-iodophenyl) dimethyl amine: ¹H NMR (CDCl₃): δ6.98 (dd, 1H), 2.82 (d, 6H).

2,4,6-Trifluoro-3-iodobenzonitrile: LC/MS (m/z=283).

1-Bromo-3,5-difluoro-4-iodo-2-methoxybenzene: LC/MS (m/z=349).

1,3-Dichloro-5-fluoro-4-iodo-2-methoxybenzene: GC-MS (m/z=320).

29. Preparation of 1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene

To a solution of 1-chloro-3,5-difluoro-2-methoxybenzene (2.0 g, 0.01mol) in THF at −75° C. was added n-butyl lithium (2.5M in hexanes 6.7mL) and the resulting solution was stirred at −75° C. for 1 hour. Asolution of iodine (5.1 g, 0.02 mol) in THF (10 mL) was added and thereaction mixture was allowed to warm to ambient temperature. Thereaction mixture was diluted with ethyl ether (50 mL) and aqueous sodiumthiosulfate (10%, 50 mL) was added and stirred for 1 hour. Afterseparating the phases, the organic phase was dried (Na₂SO₄) andconcentrated to give 1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene as awhite solid: mp 62-64° C.

The following compound was prepared according to the procedure inExample 29.

1-Chloro-2-ethoxy-3,5-difluoro-4-iodobenzene: GC-MS (m/z=178).

30. Preparation of 3-fluoro-4-iodo-2-methoxybenzonitrile

Sodium hydride (60 mg, 2.5 mmol) was slurried in DMF (15 mL) and treatedwith dry methanol (120 μl, 96 mg, 3.0 mmol). After stirring for 10minutes at 25° C., the solution was cooled to −25° C. and treated with2,3-difluoro-4-iodobenzonitrile (500 mg, 1.9 mmol). After 25 minutes,the mixture was quenched by addition of 10% citric acid solution (5 mL)and warmed to 25° C. The mixture was extracted with ethyl ether (2×15mL), the combined ether phases washed with water (5 mL), brine, dried(sodium sulfate) and evaporated to give3-fluoro-4-iodo-2-methoxybenzonitrile (500 mg, 1.8 mmol): LC/MS(m/z=277).

31. Preparation of 3-fluoro-4-iodo-2-methoxybenzaldehyde

3-Fluoro-4-iodo-2-methoxybenzonitrile (1.0 g, 3.6 mmol) was dissolved intoluene (7 mL), cooled to 0° C. and treated in portions with 25 wt. %diisobutyl aluminum hydride (DIBAL) in toluene (3.1 ml, 4.7 mmol) After30 minutes, the reaction was quenched by addition of methanol (5 mL),poured into 1M sulfuric acid (15 mL) and extracted with ethyl acetate(2×15 mL). The combined extracts were washed with water (5 mL), brine,dried (sodium sulfate) and evaporated to give3-fluoro-4-iodo-2-methoxybenzaldehyde (450 mg, 1.6 mmol): LC/MS(m/z=260).

32. Preparation of 3-chloro-4-iodo-2-methoxyaniline

3-Chloro-2-methoxyaniline (1 g, 6.4 mmol) was dissolved in methylenechloride (10 mL) in a 250 mL round bottomed flask and treated with water(10 mL), NaHCO₃ (1.1 g, 12.7 mmol) and iodine (1.61 g, 6.4 mmol) and theresulting mixture heated to reflux for 2 hours by which time TLC(hexanes:ethyl acetate/4:1) indicated nearly complete conversion. Thereaction mixture was diluted with ethyl acetate and washed withsaturated Na₂S₂O₃. The organic layer was separated and dried (Na₂SO₄).Filtration, concentration and purification by flash silica gelchromatography (hexanes:ethyl acetate/8:1) gave 0.71 g of a red oilwhich was identified as a 2.5:1 mixture of the3-chloro-4-iodo-2-methoxyaniline and starting material: ¹H NMR (300 MHz,CDCl₃) δ 7.36 (d, 1H, J=8.4 Hz), 6.45 (d, 1H, J=8.4 Hz), 4.10 (bs, 2H),3.82 (s, 3H). Other runs with excess iodine produced similar results.The mixture was combined with a previous run and used as is withoutfurther purification.

33. Preparation of 4-chloro-2,6-difluoro-3-methylaniline

A solution of 2,6-difluoro-3-methylaniline (15 g, 105 mmol) in aceticacid (80 mL) was heated to 70° C. and a solution of sulfuryl chloride(16.0 g, 115 mmol) in acetic acid (40 mL) was added dropwise over 20minutes. The temperature was maintained for 3 hours, then cooled andconcentrated. The residue taken into water (100 mL) and the pH wasadjusted to 9 with 2N sodium hydroxide and then extracted with methylenechloride (2×75 mL) and the combined extracts washed with brine, dried(sodium sulfate) and concentrated. The residue was distilled to give4-chloro-2,6-difluoro-3-methylaniline (12.2 g, 69 mmol): bp 55°-65°C./55 mm.

34. Preparation of 1-bromo-3-chloro-4-iodo-2-methoxybenzene

A mixture of 3-chloro-2-methoxy aniline and3-chloro-4-iodo-2-methoxyaniline (2.8 g, 2.5:1) was dissolved in dioxane(20 mL) and the resulting solution cooled on an ice bath while beingtreated with 48% HBr (20 mL). The dark purple mixture was then treatedwith NaNO₂ (1.4 g, 19.5 mmol) in water (6 mL) with good stirring. After10 minutes, CuBr (5.1 g, 35.5 mmol) was added and the mixture wasremoved from the ice bath and allowed to warm to room temperature andstir for 0.5 hour. The dark purple mixture was diluted with ethylacetate and water then filtered through celite with ethyl acetate. Thelayers were separated and the organic layer was washed with saturatedsodium sulfite and saturated ammonium chloride and dried (Na₂SO₄).Filtration, concentration and purification by flash silica gelchromatography (hexanes) gave 2.95 g of a colorless oil which wasdetermined to be a 2.3:1 mixture of 1-bromo-3-chloro-2-methoxybenzeneand 1-bromo-3-chloro-4-iodo-2-methoxybenzene which was used as iswithout further purification: ¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, 1H),7.19 (d, 1H), 3.90 (s, 3H).

35. Preparation of 1-chloro-3,5-difluoro-4-trimethylsilyl-benzene

To a solution of 3,5-difluoro-1-chlorobenzene (10.0 g, 67 mmol) andtetramethylethlenediamine (TMEDA; 7.8 g, 67 mmol) in THF (75 mL) at −75°C., was added n-butyl lithium (2.5M, 68 mmol) and the resulting solutionstirred for 30 minutes. A solution of trimethylsilyl chloride (7.6 g, 70mmol) in THF (15 mL) was added and the solution allowed to warm toambient temperature and stir for 25 hours. Ammonium chloride (saturatedsolution 15 mL) was added and the mixture extracted with ethyl ether(2×100 mL) and the combined extracts washed with brine, dried (sodiumsulfate) and concentrated. The residual oil was distilled to give1-chloro-3,5-difluoro-4-trimethylsilylbenzene (13.0 g, 60 mmol): bp70-75° C.

36. Preparation of 6-chloro-2,4-difluoro-3-trimethylsilylbenzaldehyde

A solution of 1-chloro-3,5-difluoro-4-trimethylsilylbenzene (1.5 g, 6.8mmol) in THF (10 mL) was added to a solution of lithiumtetramethylpiperidine (14 mmol) in THF (15 mL) at −75° C. The solutionwas stirred for 2 hours then DMF (1.5 g, 20 mmol) was added and thesolution allowed to warm to ambient temperature. The reaction wasquenched with a saturated solution of ammonium chloride (25 mL) andextracted with ethyl ether (2×25 mL) and the combined extracts dried(sodium sulfate) and concentrated. The residue was purified bychromatography (hexanes) to give6-chloro-2,4-difluoro-3-trimethylsilylbenzaldehyde (1.4 g, 5.6 mmol):LC/MS (m/z=248).

37. Preparation of 6-chloro-2,4-difluoro-3-iodobenzaldehyde

A solution of 6-chloro-2,4-difluoro-3-trimethylsilylbenzaldehyde (600mg, 2.4 mmol) in methylene chloride (7 mL) was cooled to 0° C. andtreated with solution of iodochloride (780 mg, 4.8 mmol) in methylenechloride (10 mL) and stirred at ambient temperature for 2 hours.Additional iodochloride (900 mg) was added and the solution heated underreflux for 40 minutes. The solution was allowed to cool and was washedwith sodium bisulfite (15 ml, 5% solution), water (10 mL), and asaturated solution of sodium bicarbonate (10 mL). The organic phase wasdried (sodium sulfate) and concentrated to give6-chloro-2,4-difluoro-3-iodobenzaldehyde (620 mg, 3.9 mmol): LC/MS(m/z=302).

38. Preparation of 1-bromo-2,4-difluoro-5-methoxybenzene

To a solution of 1,3 dibromo-4,6-difluorobenzene (10.0 g, 37 mmol) inTHF (50 mL) at −20° C. was added isopropyl magnesium chloride (2.0M inTHF, 42 mmol) and the resulting solution warm to 0° C. and stirred for30 minutes. Trimethylborate (4.7 g, 45 mmol) was added and the mixturestirred at ambient temperature for 1 hour. The solution was recooled to−20° C. and peracetic acid (32%, 50 mmol) was added and the solution wasstirred for 30 minutes at ambient temperature. The solution was thenquenched with sodium bisulfite (5% solution, 75 mL) and then acidifiedwith 6 N hydrochloric acid and extracted with ethyl ether (2×75 mL).Combined extracts were dried (sodium sulfate) and concentrated. Thecrude phenol was dissolved in acetonitrile (40 mL) and potassiumcarbonate (10 g, 74 mmol) and iodomethane (5.7 g, 40 mmol) were addedand stirred at ambient temperature for 20 hours. The solution wasconcentrated and the residue taken into water (50 mL) and extracted withethyl ether (2×75 mL) and the combined extracts were washed with brine,dried (sodium sulfate), and concentrated. The residue was purified bychromatography (hexanes) to give 1-bromo-2,4-difluoro-5-methoxybenzene(2.0 g, 8.6 mmol): LC/MS (m/z=223).

39. Preparation of 2-chloro-4,6-difluoro-1-iodo-3-methoxybenzene

A solution of 4-chloro-2,6-difluoro-1-iodo-3-methoxybenzene (2.0 g, 6.6mmol) in THF (7 mL) was added to LDA (8.0 mmol) in THF (15 mL) at −55°C. and the reaction stirred for 2 hours. The solution was diluted withethyl ether (50 mL) and washed with ammonium chloride (saturatedsolution 25 mL), brine and then dried (sodium sulfate) and concentrated.The residual oil was purified by reverse phase chromatography (70%acetonitrile in water) to give2-chloro-4,6-difluoro-1-iodo-3-methoxybenzene (500 mg. 1.7 mmol): LC/MS(m/z=304).

40. Preparation 4-chloro-3-(dimethylamino)-2-fluorophenylboronic acid

N-(3-Bromo-6-chloro-2-fluorophenyl)-N,N-dimethylaniline (0.88 g 3.5mmol) was dissolved in ether (10 mL) in an oven dried, nitrogen flushed,50 mL 3-necked flask equipped with a thermometer. The solution wascooled to −60° C. under nitrogen. n-Butyl lithium (0.23 g, 3.6 mmol,1.45 mL of a 2.5M solution) was added dropwise via syringe keeping thetemperature under −55° C. After 0.5 hours, trimethylborate (0.40 g, 0.38mmol) was added via syringe and the reaction was allowed to warm to roomtemperature. 1N HCl (3.5 mL) was added and the mixture was stirred for0.5 hours. The mixture was diluted with water and ether and the etherlayer was separated and dried over Na₂SO₄. Filtration and concentrationleft 0.753 g of a foam which was triturated with hexanes. The resultingsolids were collected by filtration and dried to give4-chloro-3-(dimethylamino)-2-fluorophenylboronic acid (0.5 g, 2.3 mmol)as an off white solid: ¹H NMR (DMSO-d₆) revealed the solid to be amixture of what appears to be the boronic acid and anhydrides. The solidwas used as is without further purification or characterization.

The following compounds where prepared according the procedure inExample 40.

4-Chloro-3-(diethylamino)-2-fluorophenylboronic acid: ¹H NMR (300 MHz,DMSO d6+D₂O): δ 8.26 (bs, 2H), 7.26 (m, 2H), 3.05 (q, 4H), 0.91 (t, 6H)

2,4-Dichloro-3-dimethylaminophenylboronic acid. This material wasisolated as an oily mixture of boronic acid and anhydride and usedwithout further purification or characterization.

2-Chloro-4-fluoro-3-methoxyphenylboronic acid (used withoutpurification)

41. Preparation of[3-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-{1,3,2}dixoborolan-2-yl)-phenylmethyl amine

N-(3-bromo-6-chloro-2-fluorophenyl)-N-methylamine (0.84 g, 3.5 mmol) wasdissolved in DMF (10 mL) in a nitrogen flushed 50 mL 3-neck flask andthe resulting solution was purged with nitrogen for 0.5 hour.Bis(pinacolato)diboron (0.98 g, 3.9 mmol), potassium acetate (1.04 g,10.6 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CH₂Cl₂ complex (0.14 g, 0.18 mmol) wereadded all at once and the mixture heated to 110° C. with a nitrogenpurge of the head space through 60° C. and then under an open nitrogenatmosphere for 1.5 hours. The reaction mixture was cooled to roomtemperature and partitioned between ethyl acetate and brine and thelayers separated. The aqueous phase was extracted with ethyl acetate andthe combined organics washed with brine and dried (Na₂SO₄). Filtration,concentration and purification by flash silica gel chromatography(hexanes:ethyl acetate/5:1) gave[3-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-{1,3,2}dixoborolan-2-yl)-phenylmethyl amine (0.85 g): light green solid: ¹H NMR (300 MHz, CDCl₃): δ7.05 (m, 2H), 3.96 (bs, 1H), 3.06 (d, 3H), 1.35 (s, 12H).

42. Preparation of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-thiomethyl)-phenyl)pyridine-2-carboxylicacid methyl ester Compound 1

A solution of 4-amino-3,6-dichloropyridine-2-carboxylic acid methylester (2.6 g, 0.012 mol),2-(4-chloro-2-fluoro-3-thiomethylphenyl)-[1,3,2]-dioxaborinane (4.1 g,0.016 mol), 1,4-bis(diphenylphosphino)butane (0.610 g, 0.0015 mol) andcesium fluoride (6.7 g, 0.045 mol) in acetonitrile (75 mL) were degassedwith nitrogen for 15 minutes. Palladium acetate (0.30 g, 0.0015 mol) wasadded and the mixture heated to reflux for 4 hours. The reaction mixturewas quenched with water and extracted with ethyl acetate (2×100 mL) andthe combined extracts were dried (sodium sulfate) and concentrated. Theresidual solid was purified by chromatography (25%-40% ethyl acetate inhexanes) to give4-amino-3-chloro-6-(4-chloro-2-fluoro-3-thiomethylphenyl)pyridine-2-carboxylicacid methyl ester (2.0 g, 0.005 mol): ¹H NMR (DMSO-d₆): δ 7.78 (t, 1H),7.50 (d, 1H), 7.25 (s, 1H), 3.95 (s, 3H), 2.50 (s, 3H).

The following compounds were prepared according to the procedure ofExample 42 (in some cases the crude boronic acid was used instead of theester).

4-Amino-3-chloro-6-(4-chloro-3-cyano-2-fluorophenyl)pyridine-2-carboxylicacid methyl ester (Compound 2): mp 189-190° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxymethylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 3): mp 116-117° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-difluoromethylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 4): mp 145-146° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-fluoromethylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 5): ¹H NMR (CDCl₃): δ 8.05 (dt, 1H), 7.25(d, 1H), 7.15 (s, 1H), 5.65 (dd, 2H), 4.95 (bs, 2H), 4.00 (s, 3H).

4-Amino-3-chloro-6-(4-cyano-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 6): ¹H NMR (CDCl₃): δ 7.70 (m, 1H), 7.20(dd, 1H), 7.10 (d, 1H), 4.95 (bs, 2H), 4.00 (s, 3H).

4-Amino-3-chloro-6-(2,4-dichloro-3-ethoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 7): mp 132-133° C.

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(2,2-difluoroethoxy)phenyl]pyridine-2-carboxylicacid methyl ester (Compound 8): mp 134-136° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-5-ethoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 9): mp 115-116° C.

4-Amino-3-chloro-6-[2,4-dichloro-3-(2,2-difluoroethoxy)phenyl]pyridine-2-carboxylicacid methyl ester (Compound 10): mp 113-115° C.

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(methoxyethoxy)phenyl]pyridine-2-carboxylicacid methyl ester (Compound 11): mp 89-90° C.

4-Amino-3-chloro-5-fluoro-6-(2-fluoro-3,4-methylenedioxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 12): mp 151-152° C.

4-Amino-3-chloro-6-(2,4-dichloro-3-methylthiophenyl)pyridine-2-carboxylicacid methyl ester (Compound 13): ¹NMR (CDCl₃): ¹H NMR (CDCl₃) δ 7.45 (d,1H), 7.40 (d, 1H), 6.98 (s, 1H), 4.97 (bs, 2H), 3.98 (s, 3H), 2.44 (s,3H).

4-Amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 14): mp 172-173° C.

4-Amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-5-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 15): mp 168-169° C.

4-Amino-3-chloro-6-(4-chloro-3-dimethylamino-2-fluorophenyl)pyridine-2-carboxylicacid, methyl ester (Compound 16): mp 104-106° C.

4-Amino-3-chloro-6-[4-chloro-3-(diethylamino)-2-fluorophenyl]pyridine-2-carboxylicacid, methyl ester (Compound 17): mp 120-121° C.

43. Preparation of4-acetylamino-3-chloro-6-(4-chloro-2-fluoro-5-methoxyphenyl)pyridine-2-carboxylicacid methyl ester Compound 18

A solution of 4-acetylamino-3,6-dichloropyridine carboxylic acid methylester (4.3 g, 0.016 mol),2-(4-chloro-2-fluoro-5-methoxyphenyl)-[1,3,2]-dioxaborinane (4.5 g,0.018 mol), cesium fluoride (3.5 g, 0.025 mol), and1,4-bis(diphenylphosphino)butane (0.360 g, 0.0016 mol) in acetonitrile(100 mL) was degassed with nitrogen for 15 minutes before palladiumacetate (0.180 g, 0.0016 mol) was added and the solution heated underreflux for 18 hours. Water (150 mL) was added and the resulting solidcollected and dried to give4-acetylamino-3-chloro-6-(4-chloro-2-fluoro-5-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (4.5 g, 0.012 mol): mp 180-182° C.

The following compounds were prepared according to the procedure ofExample 43.

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 19): mp 151-152° C.

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 20): mp 159-160° C.

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 21): ¹NMR (CDCl₃): δ 9.0 (bs, 1H) 8.00 (m,1H), 7.60 (m, 1H), 7.25 (s, 1H), 4.25 (q, 2H), 4.00 (s, 3H), 2.35 (s,3H), 1.50 (t, 3H).

4-Acetylamino-3-chloro-6-(2,4-dichloro-3-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 22): ¹NMR (CDCl₃): δ 8.90 (s, 1H), 8.05 (s,1H), 7.40 (d, 1H), 7.30 (d, 1H), 4.05 (s, 3H), 3.95 (s, 3H), 2.35 (s,3H).

4-Acetylamino-3-chloro-6-(2-fluoro-3,4-methylenedioxyphenyl)pyridine-2-carboxylicacid methyl ester: mp 132-134° C.

4-Acetylamino-3-chloro-6-(2,4-dichloro-3-ethoxy-2-fluorophenyl)pyridine-2-carboxylicacid methyl ester: ¹H NMR (CDCl₃): δ 8.86 (s, 1H), 8.00 (bs, 1H), 7.37(d, 1H), 7.26 (d, 1H), 4.11 (q, 2H), 4.00 (s, 3H), 2.32 (s, 3H), 1.47(t, 3H).

4-Acetylamino-3-chloro-6-[2,4-dichloro-3-(2,2-difluoroethoxy)phenyl]pyridine-2-carboxylicacid methyl ester: ¹H NMR (CDCl₃): δ 8.81 (s, 1H), 8.10 (bs, 1H), 7.32(d, 1H), 7.29 (d, 1H), 6.16 (tt, 1H), 4.22 (td, 2H), 3.95 (s, 3H), 2.28(s, 3H).

44. Preparation of4-acetylamino-3-chloro-6-(2,4-difluoro-3-methylphenyl)-pyridine-2-carboxylicacid methyl ester Compound 23

A solution of 1-bromo-2,4-difluoro-3-methylbenzene (2.10 g, 0.09 mol),4-acetylamino-3-chloro-6-trimethylstannylpyridine-2-carboxylic acidmethyl ester (4.00 g, 0.01 mol), 1,4-bis(diphenylphosphino)butane (0.140g, 0.0003 mol) and cesium fluoride (4.5 g, 0.03 mol) in acetonitrile(100 mL) was degassed with nitrogen. Palladium acetate (0.70 g, 0.0003mol) was added the solution heated to reflux for 2 hours. The reactionmixture was filtered through celite and the filtrate diluted with water(200 mL) and then extracted with ethyl acetate (2×150 mL). The combinedorganic phases were dried and concentrated and the residual solid waspurified by chromatography (50% ethyl acetate in hexanes) to give4-acetylamino-3-chloro-6-(2,4-difluoro-3-methylphenyl)-pyridine-2-carboxylicacid methyl ester (0.800 g, 0.002 mol): mp 152-153° C.

The following compound was prepared according to the procedure ofExample 44.

4-Acetylamino-3-chloro-6-(2,4-dichloro-3-methylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 24): mp 172-174° C.

45. Preparation of (2-fluoro-3-methoxy-4-trifluoromethylphenyl)trimethylstannane

Dioxane (28 mL) was added to an oven dried, nitrogen swept 100 mL 3-neckflask equipped with a condenser and a magnetic stirbar and was deaeratedwith a purge of nitrogen for 15 minutes. Hexamethylditin (5.0 g, 15.3mmol), and 1-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzene (3.8 g,13.9 mmol) were added and the purging continued for 5 minutes.1,4-bis(diphenylphosphino)butane (0.6 g, 1.4 mmol) and palladium acetate(0.3 g, 1.4 mmol) were added and the head space of the reaction vesselpurged with nitrogen while heating to reflux with stirring. The reactionwas then stirred at reflux under an open nitrogen atmosphere for 6hours. TLC (hexanes) indicated complete consumption of startingmaterial. The cooled reaction mixture was concentrated and purified byflash silica gel chromatography (hexanes) to give(2-fluoro-3-methoxy-4-trifluoromethylphenyl)trimethyl stannane (3.93 g,11.0 mmol) as an oil: ¹H NMR (CDCl₃): δ 7.31 (d, 1H), 7.11 (dd, 1H),3.98 (d, 3H), 0.38 (s, 9H). All signals had appropriate tin satellites.

The following compounds were prepared according to the procedure inExample 45.

(3-Butoxy-4-chloro-2-fluorophenyl)-trimethyl stannane (used withoutpurification).

4-Chloro-2-fluoro-3-(1-fluoro-1-methyl-ethyl)-trimethyl stannane (usedwithout purification).

46. Preparation of4-acetylamino-3-chloro-6-(2-fluoro-3-methoxy-4-trifluoromethylphenyl)pyridine-2-carboxylicacid methyl ester

In an oven dried, nitrogen flushed 100 mL 3 neck flask equipped with acondenser and a magnetic stirbar was dissolvedmethyl-4-acetamido-3,6-dichloropyridine-2-carboxylate (1.2 g, 4.6 mmol)and (2-fluoro-3-methoxy-4-trifluoromethylphenyl)trimethyl stannane (1.7g, 4.6 mmol) in acetonitrile (15 mL) and the resulting solution wasde-aerated with a purge of nitrogen for 15 minutes. Cesium fluoride (2.1g, 13.9 mmol), 1,4-bis(diphenylphosphino)butane (0.2 g, 0.46 mmol) andpalladium acetate (0.1 g, 0.46 mmol) were added and the head space ofthe reaction was purged with nitrogen as the reaction was heated toreflux with stirring. The reaction was then stirred under an opennitrogen atmosphere for 5 hours by which time TLC (hexane:ethylacetate/1:2) indicated complete consumption of starting material. Thecooled reaction was filtered through celite with ethyl acetate and thefiltrate concentrated and purified by flash silica gel chromatography(hexanes:ethyl acetate/2:1) to give4-acetylamino-3-chloro-6-(2-fluoro-3-methoxy-4-trifluoromethylphenyl)pyridine-2-carboxylicacid methyl ester (0.19 g, 0.46 mmol) as an oil: ¹H NMR (CDCl₃): δ 9.03(d, 1H), 8.02 (bs, 1H), 7.68 (bt, 1H), 7.42 (bd, 1H), 4.03 (d, 3H), 4.01(s, 3H), 2.33 (s, 3H).

The following compounds were prepared according to the procedure inExample 46.

4-Acetylamino-3-chloro-6-(4-chloro-3-butoxy-2-fluorophenyl)pyridine-2-carboxylicacid, methyl ester: LC/MS ESI (m/z=428).

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(1-fluoro-1-methylethyl)phenyl]-pyridine-2-carboxylicacid, methyl ester (Compound 25): mp 122-123° C.

47. Preparation of4-amino-3-chloro-6-(4-chloro-2-fluoro-5-nitrophenyl)-pyridine-2-carboxylicacid methyl ester

Methyl4-amino-3-chloro-6-(4-chloro-2-fluorophenyl)pyridine-2-carboxylate (1.0g, 3.2 mmol) was added as a solid to well stirred concentrated sulfuricacid (16 mL) at 0° C. Sodium nitrate (0.29 g, 3.5 mmol) was added to themixture and the resulting yellow solution was stirred at 0° C. for 1.5hours then diluted with a large quantity of ice and allowed to warm toroom temperature. The solution was filtered to remove some solids thenthe filtrate extracted with 3 portions of ethyl acetate and the combinedethyl acetate layers washed with saturated aqueous NaHCO₃ and dried(Na₂SO₄). Filtration and concentration gave4-amino-3-chloro-6-(4-chloro-2-fluoro-5-nitrophenyl)pyridine-2-carboxylicacid methyl ester (0.96 g, 2.7 mmol) as a yellow solid: mp 161-163° C.:¹H NMR (CDCl₃): δ 8.73 (d, 1H), 7.36 (d, 1H), 7.24 (d, 1H), 4.93 (bs,2H), 4.02 (s, 3H).

48. Preparation of4-amino-3-chloro-6-(5-amino-4-chloro-2-fluorophenyl)pyridine-2-carboxylicacid methyl ester

Iron powder (0.78 g, 13.9 mmol) was added to a slurry of methyl4-amino-3-chloro-6-(4-chloro-2-fluoro-5-nitrophenyl)pyridine-2-carboxylate(0.5 g, 1.39 mmol) in acetic acid (20 mL) in a 100 mL round bottomedflask. The mixture was heated to 85° C. for 15 minutes. then cooled toroom temperature and filtered through celite with ethanol and thefiltrate concentrated in vacuo. The residue was partitioned betweenethyl acetate and saturated NaHCO₃, the layers separated, the aqueousphase extracted with ethyl acetate and the combined organics dried(Na₂SO₄). Filtration and concentration gave4-amino-3-chloro-6-(5-amino-4-chloro-2-fluorophenyl)pyridine-2-carboxylicacid methyl ester (0.44 g, 1.33 mmol) as a light brown solid: mp 99-101°C.

49. Preparation of4-amino-3-chloro-6-(4-chloro-5-dimethylamino-2-fluorophenyl)pyridine-2-carboxylicacid methyl ester Compound 26

Methyl4-amino-3-chloro-6-(5-amino-4-chloro-2-fluorophenyl)-pyridine-2-carboxylate(0.38 g, 1.13 mmol)) was dissolved in THF (10 mL) in a nitrogen flushed250 mL round bottomed flask and treated with 37% formaldehyde (0.068 g,0.17 mL, 2.27 mmol), dibutyl tin dichloride (0.007 g, 0.023 mmol) andphenyl silane (0.135 g, 1.25 mmol) and allowed to stir at roomtemperature for 72 hours. The reaction mixture was concentrated in vacuoand purified by flash silica gel chromatography (hexanes:ethylacetate/2:1) to give4-amino-3-chloro-6-(4-chloro-5-dimethylamino-2-fluorophenyl)pyridine-2-carboxylicmethyl ester (0.283 g 0.8 mmol) as a soft white solid: mp 113-115° C.,¹H NMR (CDCl₃): δ 7.66 (d, 1H), 7.14 (d, 1H), 7.14 (d, 1H). 4.91 (bs,2H), 3.99 (s, 3H), 2.79 (s, 6H).

50. Preparation of 4-acetylamino-3-chloro-6-iodopyridine-2-carboxylicacid, methyl ester

To a solution of4-acetylamino-3-chloro-6-trimethyl-stannanylpyridine-2-carboxylic acid,methyl ester (21.0 g, 54 mmol) in methylene chloride (200 mL) was addediodine (13.7 g, 108 mmol) and the solution was stirred 1 hour at ambienttemperature. The solution was filtered through a bed of celite and thenwashed with sodium thiosulfate (50 mL, 10% solution), dried (sodiumsulfate) and concentrated. The residue was purified by chromatography(10% ethyl acetate in hexanes) to give4-acetylamino-3-chloro-6-iodopyridine-2-carboxylic acid, methyl ester(5.6 g, 18 mmol): GC-MS (m/z=354).

51. Preparation of 4-amino-3-chloro-6-iodopyridine-2-carboxylic acid,methyl ester

To solution of 4-acetylamino-3-chloro-6-iodopyridine-2-carboxylic acid,methyl ester (5.0 g, 14 mmol) in methanol (25 mL) was added acetylchloride (1 mL) and the solution heated under reflux for 1 hour. Thesolution was cooled and water (25 mL) added and the precipitate wascollected. Recrystallization from methanol gave4-amino-3-chloro-6-iodopyridine-2-carboxylic acid, methyl ester (3.5 g,1 mmol) mp 152-153° C.

52. Preparation of4-amino-6-(4-bromo-2-fluoro-3-methoxyphenyl)-3-chloro-pyridine-2-carboxylicacid methyl ester Compound 27

A solution of 4-amino-3-chloro-6-iodopyridine-2-carboxylic acid, methylester (1.1 g, 3.0 mmol), 4-bromo-2-fluoro-3-methoxyphenyl boronic acid(1.3 g, 4.5 mmol) and cesium fluoride (0.60 g, 4.0 mmole) indimethoxyethane (2 mL) and water (2 mL) was de-aerated with a stream ofnitrogen for 15 minutes before adding dichlorobis(triphenylphosphine)palladium (0.25 g, 0.4 mmol) and then heated to 85° C. for 2 hours. Thereaction mixture was diluted with water (15 mL) and extracted with ethylacetate (2×15 mL). The combined extracts were washed with brine, dried(sodium sulfate) and concentrated. The residue was purified bychromatography (33% ethyl acetate in hexanes) to give4-acetylamino-6-(4-bromo-2-fluoro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid, methyl ester (1.2 g, 2.8 mmol): mp 164-165° C.

The following compounds were prepared according the procedure in Example52.

4-Acetylamino-3-chloro-6-(2,4,6-trifluoro-3-methyoxyphenyl)pyridine-2-carboxylicacid, methyl ester (used without further purification).

4-Acetylamino-3-chloro-(2,4-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 28): mp 114-115° C.

4-Acetylamino-3-chloro-(2-chloro-4-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 29): mp 153-154.5° C.

53. Preparation of4-acetylamino-3-chloro-6-[2,4-dichloro-3-(1-fluoroethyl)phenyl]pyridine-2-carboxylicacid methyl ester

A solution of 2,4 dichloro-3-(1-fluoroethyl)-bromobenzene (3.4 g, 12.5mmol), 4-acetylamino-3-chloro-6-trimethylstannyl-pyridine-2-carboxylicacid, methyl ester (4.7 g, 12.5 mmol), copper iodide (0.4 g, 2.1 mmol),cesium fluoride (3.6 g, 25 mmol) anddichlorobis(triphenylphosphine)palladium (0.14 g, 2 mmol) in DMF (50 mL)was heated to 70° C. for 2 hours. Water (100 mL) was added the mixtureextracted with ethyl acetate (2×100 mL). The combined extracts werewashed with brine, dried (sodium sulfate) and concentrated. The residuewas purified by chromatography (15%-30% ethyl acetate in hexanes) togive 4-acetylamino-3-chloro-6-[2,4dichloro-3-(1-fluoroethyl)phenyl]pyridine-2-carboxylic acid, methylester which was used without further purification.

The following compounds were made according to the procedure of Example53.

4-Acetylamino-3-chloro-(2,6-difluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylicacid, methyl ester: mp 134-136° C.

4-Acetylamino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester: mp 146-147° C.

4-Acetylamino-3-chloro-6-(4-chloro-3-dimethylamino-2,6-difluorophenyl)-pyridine-2-carboxylicacid, methyl ester (used without further purification).

4-Acetylamino-3-chloro-6-(4-chloro-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (used without further purification).

4-Acetylamino-3-chloro-6-(2,4-dichloro-6-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (used without further purification).

4-Acetylamino-3-chloro-6-(4-chloro-2,6-difluoro-3-ethoxyphenyl)pyridine-2-carboxylicacid, methyl ester: (used without further purification).

4-Acetylamino-3-chloro-6-[4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl]pyridine-2-carboxylicacid, methyl ester (used without further purification).

4-Acetylamino-3-chloro-6-[2,4-dichloro-3-(difluoromethyl)phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 30): mp 152-153° C.

4-Acetylamino-3-chloro-6-(4-chloro-3-ethyl-2-fluorophenyl)pyridine-2-carboxylicacid, methyl ester: GC/PCI (m/z=236).

4-Acetylamino-3-chloro-6-[4-chloro-2-fluoro-3-(1,2,2,2-tetrafluoroethyl)-phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 31): LC/MS ESI (m/z=456).

4-Acetylamino-3-chloro-6-[4-chloro-2-fluoro-3-(1-fluoropropyl)-phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 32): LC/MS ESI (m/z=416).

4-Acetylamino-3-chloro-6-(2,3,4-trifluorophenyl)pyridine-2-carboxylicacid, methyl ester (Compound 33): mp 169-171° C.

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxymethoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 34) mp 122-123° C.

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-difluoromethoxyphenyl)pyridine,carboxylic acid, methyl ester (Compound 35): mp 146° C.

4-Acetylamino-3-chloro-6-(4-difluoromethyl-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-(2-fluoro-4-fluoromethyl-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-(4-chloro-2,6-difluoro-3-methylphenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-6-(2-bromo-4-chloro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-6-(4-bromo-2,6-difluoro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-(3-difluoromethyl-2,4,6-trifluorophenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-(2-chloro-4-difluoromethyl-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-(4-chloro-2,6-difluoro-3-difluoromethylphenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-(2-chloro-4,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-(2,4-difluoro-3-ethoxyphenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-(4-chloro-3-cyclopropyl-2-fluorophenyl)pyridine-2-carboxylicacid, methyl ester (used without purification).

4-Acetylamino-3-chloro-6-[4-chloro-2-fluoro-3-(2,2,2-trifluoroacetyl)phenyl]-pyridine-2-carboxylicacid, methyl ester (used without purification).

54. Preparation of4-amino-3-chloro-6-(2-fluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylicacid, methyl ester Compound 36

A solution of 4-amino-3,6-dichloropyridine-2-carboxylic acid, methylester (0.24 g, 1.1 mmol), 2-fluoro-3-methoxy-4-methylphenyl boronic acid(0.30 g, 1.63 mmol) and cesium fluoride (3.0 g, 3.26 mmole) indimethoxyethane (2 mL) and water (2 mL) was purged with a stream ofnitrogen for 15 minutes before adding dichlorobis(triphenylphosphine)palladium (0.07 g, 0.1 mmol) and then heated to 85° C. for 2 hours. Thereaction mixture was diluted with water (15 mL) and extracted with ethylacetate (2×15 mL). The combined extracts were washed with brine, dried(sodium sulfate) and concentrated. The residue was purified bychromatography (33% ethyl acetate in hexanes) to give4-amino-3-chloro-6-(2-fluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylicacid, methyl ester (0.08 g, 0.2 mmol): mp 95-96° C.

The following compounds were prepared according the procedure in Example52.

4-Amino-3-chloro-6-[2,4-dichloro-3-(dimethylamino)phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 37): ¹H NMR (300 MHz, CDCl₃): δ 7.30 (d,1H), 7.19 (d, 1H), 6.93 (s, 1H) 4.88 (bs, 2H), 3.96 (s, 3H), 2.88 (s,6H).

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(methylamino)phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 38): mp 148-149° C.

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(methoxycarbonyl)phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 39): ¹H NMR (300 MHz, CDCl₃): δ 7.53 (d,1H). 7.37 (d, 1H), 6.94 (s, 1H), 4.97 (bs, 2H), 3.97 (s, 3H), 3.96 (s,3H).

4-Acetylamino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester: mp 146-147° C.

4-Acetylamino-3-chloro-6-[4-chloro-3-(dimethylamino)-2,6-difluorophenyl]pyridine-2-carboxylicacid, methyl ester: ¹H NMR (300 MHz, CDCl₃): δ 8.70 (s, 1H), 8.03 (bs,1H), 7.03 (dd, 1H), 4.00 (s, 3H), 2.83 (d, 6H), 2.32 (s, 3H).

4-Acetylamino-3-chloro-6-(2,6-difluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylicacid, methyl ester: mp 134-136° C.

4-Acetylamino-6-(4-bromo-2-chloro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid, methyl ester: mp 129-130° C.

4-Acetylamino-3-chloro-6-(4-chloro-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 40): mp 144-144.5° C.

55. Preparation of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)-pyridine-2-carboxylicacid methyl ester Compound 41

To a solution of4-acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)pyridine-2-carboxylicacid methyl ester (0.5 g, 0.0013 mol) in methanol (10 mL) was addedacetyl chloride (1 mL) and the solution heated under reflux for 1 hour.Water (2 mL) was added and resulting solid collected and dried to give4-amino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)pyridine-2-carboxylicacid methyl ester: mp 154-156° C.

The following compounds were prepared according to the procedure ofExample 55.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 42): mp 141-142° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-5-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 43): ¹NMR (CDCl₃): δ 7.60 (d, 1H), 7.25 (s,1H), 7.20 (m, 1H), 4.95 (bs, 2H), 4.05 (s, 3H), 3.95 (s, 3H).

4-Amino-3-chloro-6-(2,4-dichloro-3-methoxyphenyl)pyridine-2-carboxylicacid methyl ester (Compound 44): mp 168-170° C.

4-Amino-3-chloro-6-(2-fluoro-3-methoxy-4-trifluoromethylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 45): mp 144-146° C.

4-Amino-3-chloro-6-(2-fluoro-3,4methylenedioxyphenyl)pyridine-2-carboxylic acid methyl ester (Compound46): mp 139-141° C.

4-Amino-3-chloro-6-(2,4-difluoro-3-methylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 47): mp 129-130° C.

4-Amino-3-chloro-6-(2,4-dichloro-3-methylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 48): ¹NMR (CDCl₃): 7.30 (d, 1H), 7.25 (d,1H), 6.95 (s, 1H).

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methylphenyl)pyridine-2-carboxylicacid methyl ester (Compound 49): mp 116-118° C.

4-Amino-3-chloro-6-[4-chloro-3-(dimethylamino)-2,6-difluorophenyl]pyridine-2-carboxylicacid, methyl ester (Compound 50): ¹H NMR (300 MHz, CDCl₃): δ 7.00 (dd,1H), 6.81 (s, 1H) 4.93 (bs, 2H), 3.96 (s, 3H), 2.81 (d, 6H).

4-Amino-3-chloro-6-(2,6-difluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 51): Off white foam, ¹H NMR (300 MHz,CDCl₃): δ 6.83 (s, 1H), 6.74 (dd, 1H), 4.88 (bs, 2H), 3.97 (s, 3H), 3.84(d, 3H), 2.28 (s, 3H).

4-Amino-6-(4-bromo-2-chloro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid, methyl ester (Compound 52): mp 154-155° C.

4-Amino-3-chloro-(2-chloro-4-difluoromethyl-6-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 53): LC/MS (m/z=380).

4-Amino-3-chloro-6-(4-chloro-3-difluoromethyl-2,6-difluorophenyl)pyridine-2-carboxylicacid, methyl ester (Compound 54): LC/MS (m/z=383).

4-Amino-3-chloro-(2-chloro-4,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 55): LC/MS (m/z=348).

4-Amino-3-chloro-6-(2,4,6-trifluoro-3-methyoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 56): HPLC-MS (m/z=346).

4-Amino-3-chloro-6-(2,4-dichloro-6-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 57): HPLC-MS (m/z=378).

4-Amino-3-chloro-6-(4-chloro-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 58): HPLC-MS (m/z=362).

4-Amino-3-chloro-6-(4-chloro-2,6-difluoro-3-ethoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 59): HPLC-MS (m/z=376).

4-Amino-3-chloro-6-(4-chloro-3-butoxy-2-fluorophenyl)pyridine-2-carboxylicacid, methyl ester (Compound 60): LC/MS ESI (m/z=386).

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 61): LC/MS ESI (m/z=360).

4-Amino-3-chloro-6-(2,4-dichloro-3-difluoromethylphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 62): LC/MS ESI (m/z=380).

4-Amino-3-chloro-6-[2,4-dichloro-3-(1-fluoro-1-ethylphenyl]pyridine-2-carboxylicacid, methyl ester (Compound 63): LC/MS ESI (m/z=362).

4-Amino-3-chloro-6-(4-chloro-3-ethyl-2-fluorophenyl)pyridine-2-carboxylicacid, methyl ester (Compound 64): mp 120-122° C.

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(1,2,2,2-tetrafluoroethyl)phenyl)-pyridine-2-carboxylicacid, methyl ester (Compound 65): LC/MS ESI (m/z=414).

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(1-fluoropropyl)phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 66): ¹H NMR (300 MHz, CDCl₃): δ 7.90 (m,1H), 7.25 (m, 1H), 7.10 (s, 1H), 5.96 (dq, 1H), 4.90 (bs, 2H), 4.05 (s,3H), 2.30 (m, 1H), 2.05 (m, 1H), 1.05 (t, 3H).

4-Amino-3-chloro-6-(2,3,4-trifluorophenyl)pyridine-2-carboxylic acid,methyl ester (Compound 67): mp 163-164° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxymethoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 68): mp 99° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-difluoromethoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 69): mp 164° C.

4-Amino-3-chloro-6-(2,4-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 70): LC/MS (m/z=328).

4-Amino-3-chloro-6-(4-difluoromethyl-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 71): mp 145-147° C.

4-Amino-3-chloro-6-(2-fluoro-4-fluoromethyl-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 72): LC/MS (m/z=342).

4-Amino-3-chloro-6-(2,4-difluoro-5-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 73): mp 128-130° C.

4-Amino-3-chloro-6-(2-chloro-4-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 74): mp 145-146° C.

4-Amino-3-chloro-6-(4-chloro-2,6-difluoro-3-methylphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 75): LC/MS (m/z=346).

4-Amino-6-(2-bromo-4-chloro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid, methyl ester (Compound 76): LC/MS (m/z=405).

4-Amino-6-(4-bromo-2,6-difluoro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid, methyl ester (Compound 77): LC/MS (m/z=407).

4-Amino-3-chloro-6-(3-difluoromethyl-2,4,6-trifluorophenyl)pyridine-2-carboxylicacid, methyl ester (Compound 78): LC/MS (m/z=366).

4-Amino-3-chloro-6-(2-chloro-4-difluoromethyl-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 79): mp 134-136° C.

4-Amino-3-chloro-6-(2,4-difluoro-3-ethoxyphenyl)pyridine-2-carboxylicacid, methyl ester (Compound 80): mp 158-159° C.

4-Amino-3-chloro-6-(4-chloro-3-cyclopropyl-2-fluorophenyl)pyridine-2-carboxylicacid, methyl ester (Compound 81): mp 135-136.5° C.

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(2,2,2-trifluoroacetyl)phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 82): LC/MS (m/z=410).

56. Preparation of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methanesulfinylphenyl)pyridine-2-carboxylicacid methyl ester Compound 83 And4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methanesulfonylphenyl)pyridine-2-carboxylicacid methyl ester Compound 84

To a solution of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methylthiophenyl)pyridine-2-carboxylicacid methyl ester (0.800 g, 2 mmol) in methylene chloride (20 mL) wasslowly added peracetic acid (32% in acetic acid, 0.004 mol). Thereaction mixture was quenched with sodium bisulfite (10% in water, 20mL) and extracted with methylene chloride (20 mL). The organic phase wasdried (sodium sulfate) and concentrated. The solid residue was purifiedby chromatography (15%-50% ethyl acetate in hexanes). The first fractionwas4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methanesulfonylphenyl)pyridine-2-carboxylicacid methyl ester (0.250 g, 0.7 mmole): mp 108-110° C. The secondfraction was4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methanesulfinylphenyl)pyridine-2-carboxylicacid methyl ester (0.100 g, 0.03 mmole): mp 122-124° C.

57. Preparation of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-fluoromethylthiophenyl)pyridine-2-carboxylicacid methyl ester Compound 85

To a solution of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methylthiophenyl)pyridine-2-carboxylicacid, methyl ester (1.50 g, 4.1 mmol) in acetonitrile (40 mL) was added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)(F-TEDA; SELECTFLUOR™ fluorinating agent; 1.48 g, 8.2 mmol) and thesolution was stirred at ambient temperature for 2 hours. A saturatedsolution of sodium bicarbonate (25 mL) was added the solution extractedwith methylene chloride (2×50 mL). The combined extracts were dried(sodium sulfate) and concentrated and the residue purified bychromatography (20%-50% ethyl acetate in hexanes) to give4-amino-3-chloro-6-(4-chloro-2-fluoro-3-fluoromethylthiophenyl)pyridine-2-carboxylicacid methyl ester (0.09 g, 0.2 mmol): mp 104-105° C.

58. Preparation of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylicacid, ethyl ester Compound 86

To a solution of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (200 mg, 0.9 mmol) in ethanol (5 mL) was added acatalytic amount of titanium tetraisopropoxide and the solution heatedunder reflux for 2 hours. The solution was cooled and partitionedbetween ethyl acetate (10 mL) and water (10 mL) and the organic phasewas dried (sodium sulfate) and concentrated. The residue was passed overa plug of silica gel (1:1 ethyl acetate:hexanes) to give4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, ethyl ester (150 mg. 0.6 mmol): mp 74-75° C.

The following compounds were prepared according to the procedure inExample 58.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, 2-butoxy-ethyl ester (Compound 87): LC/MS (m/z=430).

4-Amino-3-chloro-6-(4-chloro-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, butyl ester (Compound 88): LC/MS (m/z=404).

4-Amino-3-chloro-6-(2,4-dichloro-3-methoxyphenyl)pyridine-2-carboxylicacid, butyl ester (Compound 89): LC/MS ESI (m/z=402).

4-Amino-3-chloro-6-(4-bromo-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, butyl ester (Compound 90): LC/MS ESI (m/z=430).

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)pyridine-2-carboxylicacid, butyl ester (Compound 91): LC/MS ESI (m/z=402).

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, 2-butoxy-ethyl ester (Compound 92): mp 72-74° C.

59. Preparation of4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid

A slurry of4-acetylamino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine(0.13 g, 0.33 mmol) in methanol (5 mL) was treated with 1N sodiumhydroxide (1.7 mL) and stirred at ambient temperature for 1 hour. Thesolution was diluted with water (15 mL) and acidified with 1Nhydrochloric acid (1.7 mL) and the solid collected (0.095 g). Analysisby ¹H NMR showed the4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid and an impurity. This material was used without furtherpurification.

The following compounds were prepared according to the procedure ofexample 59.

4-Amino-3-chloro-6-(2,6-difluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylicacid (Compound 93): mp 167-168° C.

4-Amino-3-chloro-6-(4-chloro-2,6-difluoro-3-dimethylaminophenyl)pyridine-2-carboxylicacid (Compound 94): mp 171-172° C.

60. Preparation of4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester Compound 95

A slurry of4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid in tetrahydrofuran (10 mL) and methanol (3 mL) was treated withtrimethylsilyldiazomethane (0.64 g, 0.28 mL of a 2M solution in hexanes)at ambient temperature. After 1 hour the reaction mixture was quenchedwith acetic acid (2 mL) and water (10 mL). The mixture was extractedwith ethyl acetate (2×20 mL) and the combined extracts dried (Na₂SO₄),and concentrated. The residue was purified by chromatography (30-100%ethyl acetate in hexanes) to give4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, methyl ester (0.083 g, 0.24 mmol): ¹H NMR (CDCl₃) δ 7.15 (dd, 1H),6.85 (s, 1H), 4.98 (bs, 2H), 4.08 (d, 3 h), 3.98 (s, 3H).

61. Preparation of4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-(2,2-difluoroethoxy)phenyl)pyridine-2-carboxylicacid Compound 96

A solution of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(2,2-difluoroethoxy)phenyl)pyridine-2-carboxylicacid methyl ester (0.300 g, 0.0008 mol) in methanol (5 mL) and sodiumhydroxide (1N, 2 mL) was heated to reflux 1 hour and then acidified topH 3 (concentrated hydrochloric acid) and allowed to cool. The resultingsolid was collected and dried to give4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(2,2-difluoroethoxy)phenyl)pyridine-2-carboxylicacid (0.270 g, 0.0007 mol): mp 183-184° C. dec.

The following compounds were prepared according to the procedure ofExample 61.

4-Amino-3-chloro-(2,4-difluoro-3-methylphenyl)pyridine-2-carboxylic acid

(Compound 97): mp 189-190° C. dec.

4-Amino-3-chloro-6-(2,4-dichloro-3-methylphenyl)pyridine-2-carboxylicacid (Compound 98): mp 170-172° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methylphenyl)pyridine-2-carboxylicacid (Compound 99): mp 179-181° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid (Compound 100): mp 174-175° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-5-methoxyphenyl)pyridine-2-carboxylicacid (Compound 101): ¹NMR (DMSO-d₆): δ 13.80 (bs, 1H) 7.55 (m, 2H), 7.25(s, 1H), 3.95 (s, 3H).

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)pyridine-2-carboxylicacid (Compound 102): mp 177-178° C. dec.

4-Amino-3-chloro-6-(2,4-dichloro-3-methoxyphenyl)pyridine-2-carboxylicacid (Compound 103): mp 179-180° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methylthiophenyl)pyridine-2-carboxylicacid (Compound 104): ¹NMR (DMSO-d₆) δ 13.80 (bs, 1H), 7.90 (t, 1H), 7.55(d, 1H), 7.10 (s, 1H), 6.95 (bs, 2H), 2.50 (s, 3H).

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxymethylphenyl)pyridine-2-carboxylicacid (Compound 105): mp 187-188° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-difluoromethylphenyl)pyridine-2-carboxylicacid (Compound 106): mp 182-183° C. dec.

4-Amino-3-chloro-6-(2-fluoro-3-methoxy-4-trifluoromethylphenyl)pyridine-2-carboxylicacid (Compound 107): mp 177-178° C. dec.

4-Amino-3-chloro-6-(2-fluoro-3,4-methylenedioxyphenyl)pyridine-2-carboxylicacid (Compound 108): mp 202-203° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-5-ethoxyphenyl)pyridine-2-carboxylicacid (Compound 109): mp 178-179° C. dec.

4-Amino-3-chloro-6-(2,4-dichloro-3-methoxyphenyl)pyridine-2-carboxylicacid (Compound 110): mp 187-188° C. dec.

4-Amino-3-chloro-6-(4-chloro-5-dimethyamino-2-fluorophenyl)pyridine-2-carboxylicacid (Compound III): mp 180-181° C. dec.

4-Amino-3-chloro-6-(4-chloro-3-dimethyamino-2-fluorophenyl)pyridine-2-carboxylicacid (Compound 112): mp 185-186° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyethoxyphenyl)pyridine-2-carboxylicacid (Compound 113): mp 169-170° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-fluoromethylphenyl)pyridine-2-carboxylicacid (Compound 114): ¹H NMR (DMSO-d₆): 8.00 (dt, 1H) 7.50 (dd, 1H), 6.90(bs, 2H), 5.60 (dd, 1H).

4-Amino-3-chloro-5-fluoro-6-(2-fluoro-3,4-methylenedioxyphenyl)pyridine-2-carboxylicacid (Compound 115): mp 179-180° C.

4-Amino-3-chloro-6-[4-chloro-3-(diethylamino)-2-fluorophenyl]pyridine-2-carboxylicacid (Compound 116): mp 174-175° C.

4-Amino-3-chloro-6-[2,4-dichloro-3-(dimethylamino)phenyl]pyridine-2-carboxylicacid (Compound 117): mp 177-178° C.

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(methylamino)phenyl]pyridine-2-carboxylicacid (Compound 118): mp 185-186° C.

4-Amino-3-chloro-6-(2-fluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylicacid (Compound 119): mp 178-179° C.

4-Amino-6-(4-bromo-2-fluoro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid (Compound 120): mp 176-177° C.

4-Amino-6-(4-bromo-2-chloro-3-methoxyphenyl)-3-chloropyridine-2-carboxylicacid (Compound 121): mp 192-193° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-5-methoxyphenyl)-5-fluoropyridine-2-carboxylicacid (Compound 122): mp 180-181° C.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylicacid (Compound 123): mp 178-179° C.

4-Amino-3-chloro-6-(4-chloro-3-butoxy-2-fluorophenyl)pyridine-2-carboxylicacid (Compound 124): mp 157-158° C. dec.

4-Amino-6-[2,4 dichloro-3-(1-fluoroethyl)phenyl]pyridine-2-carboxylicacid (Compound 125): mp 169-170° C. dec.

4-Amino-3-chloro-6-(2,4-dichloro-3-difluoromethylphenyl)pyridine-2-carboxylicacid (Compound 126): mp 182-183° C. dec.

4-Amino-3-chloro-6-[2,4-dichloro-3-(1-fluoro-1-methylethylphenyl)pyridine-3-carboxylicacid (Compound 127): mp >250° C.

4-Amino-3-chloro-6-(4-chloro-3-ethyl-2-fluorophenyl)pyridine-2-carboxylicacid (Compound 128): mp 192-193° C. dec.

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(1,2,2,2-tetrafluoroethyl)-phenyl)pyridine-2-carboxylicacid (Compound 129): mp 175-176° C. dec.

4-Amino-3-chloro-6-[4-chloro-2-fluoro-3-(1-fluoropropyl)phenyl]pyridine-2-carboxylicacid, methyl ester (Compound 130): mp 165-167° C. dec.

4-Amino-3-chloro-6-(2,3,4-trifluorophenyl)pyridine-2-carboxylic acid(Compound 131): mp. 178-179° C. dec.

4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxymethoxyphenyl)pyridine-2-carboxylicacid (Compound 132): mp. 159° C. dec.

4-Amino-3-chloro-6-(4-chloro-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylicacid (Compound 133): LC/MS (m/z=293).

4-Amino-3-chloro-6-(4-chloro-3-difluoromethoxy-2-fluorophenyl)pyridine-2-carboxylicacid (Compound 134): mp 179° C. dec.

62. Preparation of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylicacid, triethyl amine salt Compound 135

To solution of4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylicacid (1.0 g, 3.1 mmol) in methanol (30 mL) was added triethylamine (10mL) and the solution stirred at ambient temperature for 1 hour and wasthen concentrated to give4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylicacid, triethylamine salt (1.1 g, 2.6 mmol): ¹NMR (DMSO-d₆): δ 7.60 (m,1H), 7.45 (m, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 3.00 (t, 6H), 1.15 (q,9H).

The following compound was prepared according to the procedure ofExample 62.

4-Amino-3-chloro-6-(2,4 dichloro-3-methoxyphenyl)pyridine-2-carboxylicacid, triethyl amine salt (Compound 136): ¹NMR (DMSO-d₆) δ 7.55 (d, 1H),7.435 (d, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 3.00 (t, 6H), 1.15 (q, 9H).

63. Preparation of Herbicidal Compositions

In the following illustrative compositions, parts and percentages are byweight.

Emulsifiable Concentrates

WT % Formulation A Compound 1 26.2 Polyglycol 26-3 5.2 Nonionicemulsifier-(di-sec-butyl)- phenyl-poly(oxypropylene)block polymer with(oxyethylene). The polyoxyethelene content is about 12 moles. WitconateP12-20 (Anionic emulsifier- 5.2 calcium dodecylbenzene sulfonate- 60 wt.% active) Aromatic 100 (Xylene range aromatic 63.4 solvent) FormulationB Compound 12 3.5 Sunspray 11N (paraffin oil) 40.0 Polyglycol 26-3 19.0Oleic acid 1.0 Xylene range aromatic solvent 36.5 Formulation C Compound14 13.2 Stepon C-65 25.7 Ethomeen T/25 7.7 Ethomeen T/15 18.0 Xylenerange aromatic solvent 35.4 Formulation D Compound 18 30.0 AgrimerAl-10LC (emulsifier) 3.0 N-methyl-2-pyrrolidone 67.0 Formulation ECompound 41 10.0 Agrimul 70-A (dispersant) 2.0 Amsul DMAP 60 (thickener)2.0 Emulsogen M (emulsifier) 8.0 Attagel 50 (suspension aid) 2.0 Cropoil 76.0

These concentrates can be diluted with water to give emulsions ofsuitable concentrations for controlling weeds.

Wettable Powders

WT % Formulation F Compound 95 26.0 Polyglycol 26-3 2.0 Polyfon H 4.0Zeosyl 100 (Precipitated hydrated SiO₂) 17.0 Barden clay + inerts 51.0Formulation G Compound 101 62.4 Polyfon H (sodium salt of lignin 6.0sulfonate) Sellogen HR (sodium naphthalene 4.0 sulfonate) Zeosyl 10027.6 Formulation H Compound 109 1.4 Kunigel V1 (carrier) 30.0 StepanolME Dry (wetter) 2.0 Tosnanon GR 31A (binder) 2.0 Kaolin NK-300 Clay(filler) 64.6

The active ingredient is applied to the corresponding carriers and thenthese are mixed and ground to yield wettable powders of excellentwettability and suspension power. By diluting these wettable powderswith water it is possible to obtain suspensions of suitableconcentrations for controlling weeds.

Water Dispersible Granules

Formulation I WT % Compound 63 26.0 Sellogen HR 4.0 Polyfon H 5.0 Zeosyl100 17.0 Kaolinite clay 48.0

The active ingredient is added to the hydrated silica, which is thenmixed with the other ingredients and ground to a powder. The powder isagglomerated with water and sieved to provide granules in the range of−10 to +60 mesh. By dispersing these granules in water it is possible toobtain suspensions of suitable concentrations for controlling weeds.

Granules

Formulation J WT % Compound 114 5.0 Celetom MP-88 95.0

The active ingredient is applied in a polar solvent such as N-methylpyrollidinone, cyclohexanone, gamma-butyrolactone, etc. to the CeletomMP 88 carrier or to other suitable carriers. The resulting granules canbe applied by hand, granule applicator, airplane, etc. in order tocontrol weeds. Formulation K WT % Compound 117 1.0 Polyfon H 8.0 NekalBA 77 2.0 Zinc Stearate 2.0 Barden Clay 87.0

All materials are blended and ground to a powder then water is added andthe clay mixture is stirred until a paste is formed. The mixture isextruded through a die to provide granules of proper size.

Water Soluble Liquids

Formulation L WT % Compound 136 3.67 Monoethanolamine pH buffer 0.5Water 95.83

The active ingredient is dissolved in an appropriate amount of water andthe additional monoethanolamine is added as a buffer. A water-solublesurfactant may be added. Other aids may be incorporated to improvephysical, chemical and/or formulation properties.

64. Evaluation of Postemergence Herbicidal Activity

Seeds or nutlets of the desired test plant species were planted in SunGro MetroMix® 306 planting mixture, which typically has a pH of 6.0 to6.8 and an organic matter content of about 30 percent, in plastic potswith a surface area of 64 square centimeters. When required to ensuregood germination and healthy plants, a fungicide treatment and/or otherchemical or physical treatment was applied. The plants were grown for7-21 days in a greenhouse with an approximate 15 hour photoperiod whichwas maintained at about 23-29° C. during the day and 22-28° C. duringthe night. Nutrients and water were added on a regular basis andsupplemental lighting was provided with overhead metal halide 1000-Wattlamps as necessary. The plants were employed for testing when theyreached the first or second true leaf stage.

A weighed amount, determined by the highest rate to be tested, of eachtest compound was placed in a 25 mL glass vial and was dissolved in 4 mLof a 97:3 v/v (volume/volume) mixture of acetone and dimethyl sulfoxide(DMSO) to obtain concentrated stock solutions. If the test compound didnot dissolve readily, the mixture was warmed and/or sonicated. Theconcentrated stock solutions obtained were diluted with 20 mL of anaqueous mixture containing acetone, water, isopropyl alcohol, DMSO,Atplus 411F crop oil concentrate, and Triton® X-155 surfactant in a48.5:39:10:1.5:1.0:0.02 v/v ratio to obtain spray solutions containingthe highest application rates. Additional application rates wereobtained by serial dilution of 12 mL of the high rate solution into asolution containing 2 mL of 97:3 (v/v) mixture of acetone and dimethylsulfoxide (DMSO) and 10 mL of an aqueous mixture containing acetone,water, isopropyl alcohol, DMSO, Atplus 411F crop oil concentrate, andTriton X-155 surfactant in a 48.5:39:10:1.5:1.0:0.02 (v/v) ratio toobtain 1/2X, 1/4X, 1/8X and 1/16X rates of the high rate. Compoundrequirements are based upon a 12 mL application volume at a rate of 187L/ha. Formulated compounds were applied to the plant material with anoverhead Mandel track sprayer equipped with a 8002E nozzles calibratedto deliver 187 L/ha over an application area of 0.503 square meters at aspray height of 18 inches (43 cm) above the average plant canopy height.Control plants were sprayed in the same manner with the solvent blank.

The treated plants and control plants were placed in a greenhouse asdescribed above and watched by sub-irrigation to prevent wash-off of thetest compounds. After 14 days, the condition of the test plants ascompared with that of the untreated plants was determined visually andscored on a scale of 0 to 100 percent where 0 corresponds to no injuryand 100 corresponds to complete kill.

By applying the well-accepted probit analysis as described by J. Berksonin Journal of the American Statistical Society, 48, 565 (1953) and by D.Finney in “Probit Analysis” Cambridge University Press (1952), the abovedata can be used to calculate GR₅₀ and GR₈₀ values, which are defined asgrowth reduction factors that correspond to the effective dose ofherbicide required to kill or control 50 percent or 80 percent,respectively, of a target plant.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Table 1. TABLE 1 Post-emergent controlof weeds. Rate % Control Compound # (g ai/ha) ABUTH AMARE CHEAL 1 140 85100 100 2 140 85 90 80 3 140 100 100 80 4 140 100 100 85 5 140 100 35 906 140 90 100 95 7 140 100 90 95 8 140 80 100 95 9 140 85 100 100 10 14090 100 100 11 140 90 95 80 12 140 100 100 100 13 140 100 100 90 14 140100 100 100 15 140 100 100 100 16 140 100 100 100 17 140 100 100 100 25140 100 100 100 26 140 100 100 100 27 140 100 90 100 28 140 100 100 9529 140 95 40 98 30 140 100 90 95 32 140 60 80 50 33 140 95 95 90 36 140100 100 100 37 140 100 100 100 38 140 100 100 100 39 140 90 75 95 40 14095 95 100 41 140 95 85 98 42 140 100 100 100 43 140 100 100 100 44 140100 100 100 45 140 100 80 95 46 140 100 100 95 47 140 100 100 100 48 10198 80 85 49 140 100 80 90 50 140 100 100 100 51 140 100 100 100 52 140100 100 95 53 140 70 80 95 54 140 100 100 100 55 140 100 100 90 56 140100 100 100 57 140 100 100 100 58 140 100 100 100 59 140 100 90 90 60140 55 90 90 61 140 100 100 100 62 140 100 100 100 63 140 100 100 100 64140 95 100 100 65 140 95 100 90 66 140 90 100 95 67 140 100 100 100 68140 95 100 100 69 140 100 100 100 70 140 100 100 100 71 140 100 80 85 72140 100 20 80 73 140 90 100 100 74 140 100 90 100 75 140 100 95 95 76140 100 100 100 77 140 100 100 100 78 140 90 100 100 79 140 95 90 100 80140 100 100 95 81 140 100 100 95 82 140 100 100 95 83 140 90 85 85 84140 80 75 70 85 140 100 95 100 86 140 100 100 100 87 140 100 100 100 90140 100 85 100 91 140 95 100 100 92 140 100 100 100 93 140 100 100 10094 140 100 100 100 95 140 100 85 90 96 140 50 100 90 97 140 65 85 80 98140 90 70 80 99 140 80 90 90 100 140 100 100 100 101 140 100 100 100 102140 80 85 95 103 140 95 100 100 104 140 85 80 80 105 140 95 98 85 106140 90 100 90 107 140 100 80 90 108 140 100 100 95 110 140 80 90 85 112140 100 100 100 114 140 95 85 95 115 140 100 100 100 116 140 80 90 100117 140 100 100 100 118 140 100 100 100 119 140 100 100 95 120 140 10090 95 121 140 100 95 90 123 140 100 100 100 126 140 90 100 100 127 14090 100 100 129 140 85 95 90 130 140 80 95 95 131 140 100 100 100 134 14095 100 90ABUTH = velvetleaf (Abutilon theophrasti)AMARE = redroot pigweed (Amaranthus retroflexus)CHEAL = lambsquarter (Chenopodium album)

65. Evaluation of Preemergence Herbicidal Activity

Seeds of the desired test plant species were planted in a soil matrixprepared by mixing a loam soil (43 percent silt, 19 percent clay, and 38percent sand, with a pH of about 8.1 and an organic matter content ofabout 1.5 percent) and sand in a 70 to 30 ratio. The soil matrix wascontained in plastic pots with a surface area of 113 square centimeters.When required to ensure good germination and healthy plants, a fungicidetreatment and/or other chemical or physical treatment was applied.

A weighed amount, determined by the highest rate to be tested, of eachtest compound was placed in a 25 mL glass vial and was dissolved in 6 mLof a 97:3 v/v (volume/volume) mixture of acetone and DMSO to obtainconcentrated stock solutions. If the test compound did not dissolvereadily, the mixture was warmed and/or sonicated. The stock solutionsobtained were diluted with 18 mL of a 0.1% v/v aqueous solution ofTween® 20 surfactant to obtain spray solutions containing the highestapplication rate. Additional application rates were obtained by serialdilution of 12 mL of the high rate solution into a solution containing 3mL of 97:3 v/v (volume/volume) mixture of acetone and DMSO and 9 mL ofthe 0.1% v/v aqueous solution of Tween® 20 surfactant to obtain 1/2X,1/4X, 1/8X and 1/16X rates of the high rate. Compound requirements arebased upon a 12 mL application volume at a rate of 187 L/ha. Formulatedcompounds were applied to the plant material with an overhead Mandeltrack sprayer equipped with a 8002E nozzles calibrated to deliver 187L/ha over an application area of 0.503 square meters at a spray heightof 18 inches (43 cm) above the soil surface. Control plants were sprayedin the same manner with the solvent blank.

The treated pots and control pots were placed in a greenhouse maintainedwith an approximate 15 hour photoperiod and temperatures of about 23-29°C. during the day and 22-28° C. during the night. Nutrients and waterwere added on a regular basis and supplemental lighting was providedwith overhead metal halide 1000-Watt lamps as necessary. The water wasadded by top-irrigation. After 20-22 days, the condition of the testplants that germinated and grew as compared with that of the untreatedplants that emerged and grew was determined visually and scored on ascale of 0 to 100 percent where 0 corresponds to no injury and 100corresponds to complete kill or no emergence.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Table 2. TABLE 2 Pre-emergent controlof weeds. Rate % Control Compound # (g ai/ha) ABUTH AMARE CHEAL 1 140 80100 90 3 140 98 100 95 10 280 40 50 80 12 140 100 100 100 14 140 100 100100 15 140 60 100 100 16 140 90 100 100 26 140 10 10 90 27 140 100 10090 41 140 80 50 90 42 140 100 100 100 43 140 98 100 100 44 140 95 30 9549 140 100 100 99 50 140 100 100 100 52 140 100 100 90 58 140 100 100100 59 140 90 100 60 62 140 100 100 100 63 140 100 100 100 64 140 80 100100 70 140 100 100 100 74 140 100 95 95 77 140 100 100 100 82 140 90 100100 93 140 100 100 100 94 140 100 100 100 95 140 90 90 90 96 140 20 7040 99 140 100 100 95 100 140 100 100 100 101 140 100 100 100 102 140 8595 0 103 123 90 100 100 104 140 100 100 80 105 140 100 100 95 108 140 90100 90 110 140 100 40 40 111 140 35 100 100 112 140 100 100 100 113 1400 0 55 115 140 100 100 100 116 140 100 100 75 121 140 100 100 100 122140 100 100 100 123 140 100 100 100 125 140 100 100 100 131 140 90 100100ABUTH = velvetleaf (Abutilon theophrasti)AMARE = redroot pigweed (Amaranthus retroflexus)CHEAL = lambsquarter (Chenopodium album)

66. Evaluation of Herbicidal Activity in Transplanted Paddy Rice

Weed seeds or nutlets of the desired test plant species were planted inpuddled soil (mud) prepared by mixing a non-sterilized mineral soil (28percent silt, 18 percent clay, and 54 percent sand, with a pH of about7.3 to 7.8 and an organic matter content of about 1.0 percent) and waterat a ratio of 100 kg of soil to 19 L of water. The prepared mud wasdispensed in 250 mL aliquots into 480 mL non-perforated plastic potswith a surface area of 91.6 square centimeters leaving a headspace of 3centimeters in each pot. Rice seeds were planted in Sun Gro MetroMix®306 planting mixture, which typically has a pH of 6.0 to 6.8 and anorganic matter content of about 30 percent, in plastic plug trays.Seedlings at the second or third leaf stage of growth were transplantedinto 650 mL of mud contained in 960 mL non-perforated plastic pots witha surface area of 91.6 square centimeters 4 days prior to herbicideapplication. The paddy was created by filling the 3 centimeter headspaceof the pots with water. When required to ensure good germination andhealthy plants, a fungicide treatment and/or other chemical or physicaltreatment was applied. The plants were grown for 4-14 days in agreenhouse with an approximate 14 hour photoperiod which was maintainedat about 29° C. during the day and 26° C. during the night. Nutrientswere added as Osmocote (17:6:10, N:P:K+ minor nutrients) at 2 g per pot.Water was added on a regular basis to maintain the paddy flood, andsupplemental lighting was provided with overhead metal halide 1000-Wattlamps as necessary. The plants were employed for testing when theyreached the second or third true leaf stage.

A weighed amount, determined by the highest rate to be tested, of eachtest compound was placed in a 120 mL glass vial and was dissolved in 20mL of acetone to obtain concentrated stock solutions. If the testcompound did not dissolve readily, the mixture was warmed and/orsonicated. The concentrated stock solutions obtained were diluted with20 mL of an aqueous mixture containing 0.01% Tween 20 (v/v). Applicationrates of 1/2X, 1/4X, 1/8X and 1/16X of the high rate were obtained byinjecting an appropriate amount of the stock solution into the aqueouslayer of the paddy. Control plants were treated in the same manner withthe solvent blank.

The treated plants and control plants were placed in a greenhouse asdescribed above and water was added as needed to maintain a paddy flood.After 3 weeks the condition of the test plants as compared with that ofthe control plants was determined visually and scored on a scale of 0 to100 percent where 0 corresponds to no injury and 100 corresponds tocomplete kill.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Table 3. TABLE 3 Herbicidal Activity inTransplant Rice. Rate % Control Compound # (g ai/ha) ORYSA ECHCG MOOVACYPDI SCPJU 4 17.5 0 0 100 95 70 5 70 0 20 100 100 90 7 70 10 100 100100 85 17 35 0 70 100 100 90 27 17.5 0 45 100 100 99 38 70 0 50 100 10095 41 17.5 10 50 100 100 90 42 17.5 5 40 100 100 90 44 70 0 50 90 100 9546 35 0 20 100 100 100 52 70 0 60 99 100 95 58 17.5 0 30 100 100 50 6135 0 80 100 100 100 70 70 0 45 100 95 95 77 35 0 70 100 100 99 86 70 1025 100 100 95 88 70 10 100 100 100 100 89 70 0 85 100 100 90 90 17.5 030 100 100 90 91 35 0 99 100 100 99 92 17.5 0 40 100 99 90 100 17.5 1030 100 100 80 103 70 10 40 100 100 95 120 35 0 40 100 100 95 125 70 5100 100 100 100 135 17.5 10 30 100 100 85 136 35 0 15 100 100 80ORYSA = rice (Orysa sativa var. Japonica)ECHCG = Echinochloa crus-galliSCPJU = Scirpus juncoidesCYPDI = Cyperus difformisMOOVA = Monochoria vaginalis

67. Evaluation of Postemergence Herbicidal Activity in Cereal Crops

Seeds of the desired test plant species were planted in Sun GroMetroMix® 306 planting mixture, which typically has a pH of 6.0 to 6.8and an organic matter content of about 30 percent, in plastic pots witha surface area of 103.2 square centimeters. When required to ensure goodgermination and healthy plants, a fungicide treatment and/or otherchemical or physical treatment was applied. The plants were grown for7-36 days in a greenhouse with an approximate 14 hour photoperiod whichwas maintained at about 18° C. during the day and 17° C. during thenight. Nutrients and water were added on a regular basis andsupplemental lighting was provided with overhead metal halide 1000-Wattlamps as necessary. The plants were employed for testing when theyreached the second or third true leaf stage.

A weighed amount, determined by the highest rate to be tested, of eachtest compound was placed in a 25 mL glass vial and was dissolved in 8 mLof a 97:3 v/v mixture of acetone and DMSO to obtain concentrated stocksolutions. If the test compound did not dissolve readily, the mixturewas warmed and/or sonicated. The concentrated stock solutions obtainedwere diluted with 16 mL of an aqueous mixture containing acetone, water,isopropyl alcohol, DMSO, Agri-dex crop oil concentrate, and Triton® X-77surfactant in a 64.7:26.0:6.7:2.0:0.7:0.01 v/v ratio to obtain spraysolutions containing the highest application rates. Additionalapplication rates were obtained by serial dilution of 12 mL of the highrate solution into a solution containing 4 mL of 97:3 v/v mixture ofacetone and DMSO and 8 mL of an aqueous mixture containing acetone,water, isopropyl alcohol, DMSO, Agri-dex crop oil concentrate, andTriton X-77 surfactant in a 48.5:39.0:10.0:1.5:1.0:0.02 v/v ratio toobtain 1/2X, 1/4X, 1/8X and 1/16X rates of the high rate. Compoundrequirements are based upon a 12 mL application volume at a rate of 187Uha. Formulated compounds were applied to the plant material with anoverhead Mandel track sprayer equipped with a 8002E nozzles calibratedto deliver 187 L/ha over an application area of 0.503 square meters at aspray height of 18 inches (43 cm) above average plant canopy height.Control plants were sprayed in the same manner with the blank.

The treated plants and control plants were placed in a greenhouse asdescribed above and watered by sub-irrigation to prevent wash-off of thetest compounds. After 20-22 days, the condition of the test plants ascompared with that of the control plants was determined visually andscored on a scale of 0 to 100 percent where 0 corresponds to no injuryand 100 corresponds to complete kill.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Table 4. TABLE 4 Post-emergent Controlof Several Key Weeds in Cereal Crops Rate % Control Compound # (g ai/ha)TRZAS  HORVS GALAP LAMPU PAPRH  VERPE 1 35 5 10 85 80 80 50 14 35 0 0 9095 95 65 16 17.5 10 10 95 100 95 95 17 17.5 0 0 80 100 100 99 26 70 0 1080 95 95 40 27 17.5 5 5 99 100 100 50 36 70 5 0 95 99 99 50 38 17.5 5 085 95 100 99 42 17.5 5 5 99 100 99 60 43 70 0 5 65 99 85 30 44 35 10 565 99 90 60 45 17.5 0 0 90 100 90 80 50 70 0 0 95 100 95 60 51 35 0 0 9570 100 30 56 70 0 10 100 99 100 95 58 17.5 0 0 100 100 99 60 61 17.5 100 85 99 90 75 65 35 15 5 85 95 90 40 70 17.5 0 0 99 100 99 60 71 17.5 00 95 95 95 50 73 70 0 0 95 99 95 60 77 17.5 0 0 99 100 99 65 87 17.5 0 0100 100 100 50 90 17.5 0 10 99 100 95 25 91 17.5 20 10 90 100 60 45 9217.5 0 0 99 100 95 30 100 17.5 10 5 90 100 95 65 101 70 10 5 60 99 10060 103 35 0 0 60 95 100 75 120 17.5 0 0 80 95 95 50 133 17.5 0 0 100 99100 70 135 17.5 0 0 90 100 100 60TRZAS = wheat (Triticum aestivum)HORVS = barley (Hordeum vulare)GALAP = Galium aparineLAMPU = Lamium purpureumPAPRH = Papaver rhoeasVERPE = Veronica persica

68. Evaluation of Postemergence Herbicidal Safening in Cereal Crops

Seeds of the desired test plant species were planted in Sun GroMetroMix® 306 planting mixture, which typically has a pH of 6.0 to 6.8and an organic matter content of about 30 percent, in plastic pots witha surface area of 103.2 square centimeters. When required to ensure goodgermination and healthy plants, a fungicide treatment and/or otherchemical or physical treatment was applied. The plants were grown for7-36 days in a greenhouse with an approximate 14 hour photoperiod whichwas maintained at about 18° C. during the day and 17° C. during thenight. Nutrients and water were added on a regular basis andsupplemental lighting was provided with overhead metal halide 1000-Wattlamps as necessary. The plants were employed for testing when theyreached the second or third true leaf stage.

Treatments consisted of compound 42 and cloquintocet-mexyl alone and incombination. Weighed amounts were placed in 25 mL glass vials anddissolved in a volume of 97:3 v/v acetone/DMSO to obtain 9 mg ai/mLstock solutions. If the test compound did not dissolve readily, themixture was warmed and/or sonicated. The concentrated stock solutionswere diluted to 3 mg ai/mL with the addition of 2 volumes of an aqueousmixture containing acetone, water, isopropyl alcohol, DMSO, Agri-dexcrop oil concentrate, and Triton® X-77 surfactant in a64.7:26.0:6.7:2.0:0.7:0.01 v/v ratio. A dilution solution was preparedby mixing 1 volume of 97:3 v/v acetone/DMSO and 2 volumes of an aqueousmixture containing acetone, water, isopropyl alcohol, DMSO, Agri-dexcrop oil concentrate, and Triton® X-77 surfactant in a64.7:26.0:6.7:2.0:0.7:0.01 v/v ratio. Compound requirements are basedupon a 12 μL application volume at a rate of 187 L/ha. Spray solutionsof cloquintocet-mexyl and compound 42 mixtures were prepared by addingthe stock solutions to the appropriate amount of dilution solution toform 12 mL spray solution with active ingredients at 1:1, 1:2, and 1:4(herbicide:safener) ratios. Formulated compounds were applied to theplant material with an overhead Mandel track sprayer equipped with a8002E nozzles calibrated to deliver 187 L/ha over an application area of0.503 square meters at a spray height of 18 inches (43 cm) above averageplant canopy height. Control plants were sprayed in the same manner withthe solvent blank.

The treated plants and control plants were placed in a greenhouse asdescribed above and watered by sub-irrigation to prevent wash-off of thetest compounds. After 3 weeks the condition of the test plants ascompared with that of the untreated plants was determined visually andscored on a scale of 0 to 100 percent where 0 corresponds to no injuryand 100 corresponds to complete kill.

Colby's equation was used to determine the herbicidal effects expectedfrom the mixtures (Colby, S. R. 1967. Calculation of the synergistic andantagonistic response of herbicide combinations. Weeds 15:20-22).

The following equation was used to calculate the expected activity ofmixtures containing two active ingredients, A and B:Expected=A+B−(A×B/100)

A=observed efficacy of active ingredient A at the same concentration asused in the mixture.

B=observed efficacy of active ingredient B at the same concentration asused in the mixture.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Table 5. TABLE 5 Safening of herbicidalinjury on cereal crops Application Rate (g ai/ha) % Control CompoundCloquintocet- TRZAS HORVW GALAP PAPRH #42 mexyl Ob Ex Ob Ex Ob Ex Ob Ex35 0 35 — 0 — 99 — 100 — 70 0 40 — 15 — 100 — 100 — 0 35 0 — 0 — 0 — 0 —0 70 0 — 0 — 0 — 0 — 0 140 0 — 0 — 0 — 0 — 0 280 0 — 0 — 0 — 0 — 35 35 035 0 0 100 99 100 100 35 70 0 35 0 0 100 99 100 100 35 140 0 35 0 0 10099 100 100 70 70 0 40 0 15 100 100 100 100 70 140 0 40 0 15 100 100 100100 70 280 0 40 0 15 100 100 100 100TRZAS = Triticum aestivum (spring wheat)HORVW = Hordeum vulgare (winter barley)GALAP = Galium aparinePAPRH = Papaver rhoeasOb = observed valuesEx = expected, calculated values

69. Evaluation of Postemergence Herbicidal Activity of Mixtures inCereal

Seeds of the desired test plant species were planted and reared asdescribed in “Evaluation of Postemergence Herbicidal Safening in CerealCrops” (section 37).

Treatments consisted of compound (as listed in Tables 6 and 7),fluroxypyr methylheptyl ester (MHE), and clopyralid monoethanolamine(MEA) salt alone and in combination. Weighed amounts were placed in 25mL glass vials and dissolved in a volume of 97:3 v/v acetone/DMSO toobtain 4.5 mg ai/mL stock solutions. If the experimental compound didnot dissolve readily, the mixture was warmed and/or sonicated. Theconcentrated stock solutions were diluted to 1.5 mg ai/mL with theaddition of 2 volumes of an aqueous mixture containing acetone, water,isopropyl alcohol, DMSO, Agri-dex crop oil concentrate, and Triton® X-77surfactant in a 64.7:26.0:6.7:2.0:0.7:0.01 v/v ratio. A dilutionsolution was prepared by mixing 1 volume of 97:3 v/v acetone/DMSO and 2volumes of an aqueous mixture containing acetone, water, isopropylalcohol, DMSO, Agri-dex crop oil concentrate, and Triton® X-77surfactant in a 64.7:26.0:6.7:2.0:0.7:0.01 v/v ratio. Compoundrequirements are based upon a 12 mL application volume at a rate of 187L/ha. Spray solutions of fluoroxypyr MHE, clopyralid MEA, andexperimental compound mixtures were prepared by adding the stocksolutions to the appropriate amount of dilution solution to form 12 mLspray solution with active ingredients in two- and three-waycombinations. Formulated compounds were applied to the plant materialwith an overhead Mandel track sprayer equipped with a 8002E nozzlescalibrated to deliver 187 L/ha over an application area of 0.503 squaremeters at a spray height of 18 inches (43 cm) above average plantcanope. Control plants were sprayed in the same manner with the solventblank.

The treated plants and control plants were placed in a greenhouse asdescribed above and watered by sub-irrigation to prevent wash-off of thetest compounds. After 3 weeks the condition of the test plants ascompared with that of the control plants was determined visually andscored on a scale of 0 to 100 percent where 0 corresponds to no injuryand 100 corresponds to complete kill.

Colby's equation was used to determine the herbicidal effects expectedfrom the mixtures (Colby, S. R. 1967. Calculation of the synergistic andantagonistic response of herbicide combinations. Weeds 15:20-22).

The following equation was used to calculate the expected activity ofmixtures containing two active ingredients, A and B:Expected=A+B−(A×B/100)

A=observed efficacy of active ingredient A at the same concentration asused in the mixture.

B=observed efficacy of active ingredient B at the same concentration asused in the mixture.

The following equation was used to calculate the expected activity ofmixtures containing three active ingredients, A, B, and C:Expected=A+B+C−(A×B+B×C+A×C)/100+(A×B×C)/10000

A=observed efficacy of active ingredient A at the same concentration asused in the mixture.

B=observed efficacy of active ingredient B at the same concentration asused in the mixture.

C=observed efficacy of active ingredient C at the same concentration asused in the mixture.

Some of the compounds tested, application rates employed, plant speciestested, and results are given in Table 6 and Table 7. TABLE 6 Safeningand synergistic activity of herbicidal combinations. Application Rate (gai/ha) % Control Compound Compound Compound Fluroxypyr Clopyralid TRZASHORVW MATCH #93 #74 #58 MHE MEA Ob Ex Ob Ex Ob Ex 0 0 0 0 35 0 — 0 — 20— 0 0 0 35 0 0 — 0 — 0 — 0 0 0 35 35 0  0 0  0 25 20 35  — — 0 0 15 — 10— 45 — 35  — — 35 35 0 15 0 10 85 56 — 35  — 0 0 25 — 0 — 10 — — 35  —35 35 10 25 0  0 80 28 — — 35  0 0 35 — 15 — 0 — — — 35  35 35 30 35 1015 70 20TRZAS = Triticum aestivum (spring wheat)HORVW = Hordeum vulgare (winter barley)MATCH = Matricaria chamomillaMHE = methyl heptyl esterMEA = monoethanolamine saltOb = observed valuesEx = expected, calculated values

TABLE 7 Safening and synergistic activity of herbicidal combinations.Application Rate (g ai/ha) Com- % Control pound Clopyralid FluroxypyrTRZAS HORVW MATCH #42 MEA MHE Ob Ex Ob Ex Ob Ex 35 0 0 30 — 25 — 50 — 700 0 45 — 30 — 60 — 0 35 0 0 — 0 — 5 — 0 70 0 0 — 0 — 40 — 0 0 35 0 — 0 —0 — 0 0 70 0 — 0 — 0 — 0 35 35 0  0 0  0 20  5 0 70 70 0  0 0  0 20 4035 35 0 25 30 15 30 99 52 70 70 0 40 45 25 30 100 76 35 0 35 30 30 15 250 50 70 0 70 35 45 20 30 90 60 35 35 35 30 30 15 25 70 52 70 70 70 30 4525 30 99 76 35 70 35 20 30 15 25 99 70 35 35 70 10 30 15 25 99 52 70 3535 30 45 25 30 70 62TRZAS = Triticum aestivum (spring wheat)HORVW = Hordeum vulgare (winter barley)MATCH = Matricaria chamomillaMHE = methyl heptyl esterMEA = monoethanolamine saltOb = observed valuesEx = expected, calculated values

1-17. (canceled)
 18. A compound of the formulaArL wherein Ar represents a polysubstituted aryl group selected from thegroup consisting of

wherein W₁ represents halogen; X₁ represents F, Cl, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy-substituted C₁-C₄ alkyl, C₁-C₄alkoxy-substituted C₁-C₄ alkoxy, —CN, —NR₃R₄ or fluorinated acetyl orpropionyl; Y₁ represents C₁-C₄ alkyl, C₁-C₄ haloalkyl, halogen or —CN,or, when X₁ and Y₁ are taken together, represents —O(CH₂)_(n)O— whereinn=1 or 2; and R₃ and R₄ independently represent H or C₁-C₄ alkyl;

wherein W₂ represents F or Cl; X₂ represents F, Cl, —CN, —NO₂, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄alkoxy-substituted C₁-C₄ alkyl, C₁-C₄ alkoxy-substituted C₁-C₄ alkoxy,—NR₃R₄ or fluorinated acetyl or propionyl; Y₂ represents halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl or —CN, or, when W₂ represents F, X₂ and Y₂ takentogether represent —O(CH₂)_(n)O— wherein n=1 or 2; and R₃ and R₄independently represent H or C₁-C₆ alkyl; and

wherein Y₃ represents halogen, —CN or —CF₃; Z₃ represents F, Cl, —CN,—NO₂, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄alkoxy-substituted C₁-C₄ alkyl, C₁-C₄ alkoxy-substituted C₁-C₄ alkoxy,—NR₃R₄ or fluorinated acetyl or propionyl; and R₃ and R₄ independentlyrepresent H, or C₁-C₆ alkyl; and L represents a leaving group selectedfrom the group consisting of Cl, Br, I and trifluoromethanesulfonate.19. A compound according to claim 18 selected from the group consistingof: 3-Bromo-6-chloro-2-fluorophenol;3-Bromo-2-fluoro-6-trifluoromethylphenol;3-Bromo-2-chloro-6-fluorophenol;1-Bromo-4-chloro-2-fluoro-3-methoxybenzene;1-Bromo-4-chloro-3-ethoxy-2-fluorobenzene;1-Bromo-4-chloro-2-fluoro-3-isopropropoxybenzene;1-Bromo-4-chloro-2-fluoro-3-(2-methoxyethoxy)benzene;1-Bromo-2-fluoro-3-methoxy-4-trifluoromethylbenzene;1-Bromo-2,4-dichloro-3-ethoxybenzene;1-Bromo-3-butoxy-4-chloro-2-fluorobenzene;1-Bromo-4-chloro-2-fluoro-3-methoxymethoxybenzene;1-Bromo-2-chloro-4-fluoro-3-methoxybenzene;1-Bromo-4-chloro-2-fluoro-3-difluoromethoxybenzene;1-Bromo-4-chloro-3-(2,2-difluoroethoxy)-2-fluorobenzene;1-Bromo-2,4-dichloro-3-(2,2-difluoroethoxy)benzene;1-Bromo-4-chloro-2-fluoro-3-(methylthio)benzene;1-Bromo-2,4-dichloro-3-(methylthio)benzene;1-(3-Bromo-6-chloro-2-fluorophenyl)-1-ethanol;3-Bromo-2,4-dichlorobenzaldehyde;1-(3-Bromo-2,6-dichlorophenyl)-1-ethanol;1-Bromo-4-chloro-3-ethyl-2-fluoro-benzene;1-(3-Bromo-6-chloro-2-fluoro-phenyl)-2,2,2-trifluoroethanone;1-(3-Bromo-6-chloro-2-fluorophenyl)-1-propanol;2-(3-Bromo-6-chloro-2-fluorophenyl)-2-propanol;1-Bromo-4-chloro-2-fluoro-3-difluoromethylbenzene;1-Bromo-2,4-dichloro-3-difluoromethylbenzene;1-Difluoromethyl-3-fluoro-4-iodo-2-methoxybenzene;N-Pivaloyl-2-bromo-4-chloro-3-methoxyaniline;2-Bromo-4-chloro-1-iodo-3-methoxybenzene;4-Chloro-2,6-difluoro-5-methyl-1-iodobenzene;2-Chloro-4-difluoromethyl-3-methoxy-1-iodobenzene;1-Chloro-2-difluoromethyl-3,5-difluoro-4-iodobenzene;1-(3-Bromo-6-chloro-2-fluorophenyl)-2,2,2-trifluoroethanol;3-Fluoro-4-iodo-2-methoxyphenyl methanol;1-Bromo-4-chloro-3-fluoromethyl-2-fluorobenzene;1-Bromo-4-chloro-2-fluoro-3-(1-fluoro-1-methylethyl)benzene;1-Bromo-2,4-dichloro-3-(1-fluoroethyl)benzene;1-Bromo-4-chloro-2-fluoro-3-(1-fluoroethyl)benzene;1-Bromo-4-chloro-2-fluoro-3-(1,2,2,2-tetrafluoroethyl)benzene;1-Bromo-4-chloro-2-fluoro-3-(1-fluoropropyl)benzene;2-Fluoro-4-fluoromethyl-1-iodo-3-methoxybenzene;1-Bromo-4-chloro-2-fluoro-3-methoxymethylbenzene;1-Bromo-4-chloro-2-fluoro-3-methylbenzene;3-Bromo-6-chloro-2-fluorobenzonitrile;3-Bromo-2-fluoro-6-chlorobenzamide; 3-Bromo-6-chloro-2-fluoroaniline;3-Bromo-2,6-dichloroaniline;N-(3-Bromo-6-chloro-2-fluorophenyl)-N,N-dimethylamine;N-(3-Bromo-6-chloro-2-fluorophenyl)-N,N-diethylamine;N-(3-Bromo-2,6-dichlorophenyl)-N,N-dimethylamine;N-(3-Bromo-6-chloro-2-fluorophenyl)-N-methylamine;1,3-Difluoro-2-iodo-4-methoxy-5-methylbenzene;3,5-Difluoro-4-iodo-2-methoxybenzonitrile;N-(6-Chloro-2,4-difluoro-3-iodophenyl)-N,N-dimethylamine;1,3-Dichloro-5-fluoro-4-iodo-2-methoxybenzene;1,3-Difluoro-2-iodo-4-methoxy-5-methylbenzene;2,3-Difluoro-4-iodobenzonitrile;3-Chloro-1-difluoromethyl-5-fluoro-4-iodo-2-methoxybenzene;2-Ethoxy-1,3-difluoro-4-iodobenzene;1,3-Difluoro-2-iodo-4-methoxy-5-methylbenzene; 3,5Difluoro-4-iodo-2-methoxybenzonitrile;1-Chloro-3,5-difluoro-4-iodo-2-methoxybenzene;1-Chloro-2-ethoxy-3,5-difluoro-4-iodobenzene;3-Fluoro-4-iodo-2-methoxybenzonitrile;3-Fluoro-4-iodo-2-methoxybenzaldehyde; 3-Chloro-4-iodo-2-methoxyaniline;1-Bromo-3-chloro-4-iodo-2-methoxybenzene;(6-Chloro-2,4-difluoro-3-iodophenyl) dimethyl amine;2,4,6-Trifluoro-3-iodobenzonitrile;1-Bromo-3,5-difluoro-4-iodo-2-methoxybenzene;1,3-Dichloro-5-fluoro-4-iodo-2-methoxybenzene;6-Chloro-2,4-difluoro-3-iodobenzaldehyde;1-Bromo-2,4-difluoro-5-methoxybenzene; and2-Chloro-4,6-difluoro-1-iodo-3-methoxybenzene. 20-21. (canceled)